FIB-4 index is associated with mortality in critically ill patients with alcohol use disorder: Analysis from the MIMIC-IV database.

BACKGROUND: The relationship between fibrosis-4 (FIB-4) index and all-cause mortality in critically ill patients with alcohol use disorder (AUD) is unclear. The present study aimed to investigate the predictive ability of FIB-4 for all-cause mortality in critically ill AUD patients and the association between them. METHODS: A total of 2528 AUD patients were included using the Medical Information Mart for Intensive Care IV (MIMIC-IV) database. FIB-4 was calculated for each patient using the existing formula. The patients were equally divided into four groups based on the quartiles of FIB-4. Multivariate logistic regression and Cox proportional hazard model were used to evaluate the association of FIB-4 with in-hospital mortality, 28-day mortality and 1-year mortality. Kaplan-Meier curves were used to analyse the incidence of 28-day mortality among four groups. RESULTS: FIB-4 was positively associated with 28-day mortality of AUD patients with hazard ratio (HR) of 1.354 [95% confidence interval (CI) 1.192-1.538]. There were similar trends in the in-hospital mortality [odds ratio (OR): 1.440, 95% CI (1.239-1.674)] and 1-year mortality [HR: 1.325, 95% CI (1.178-1.490)]. CONCLUSION: Increased FIB-4 is associated with greater in-hospital mortality, 28-day mortality and 1-year mortality in critically ill AUD patients.

CH4 and N2 O emissions from smallholder agricultural systems on tropical peatlands in Southeast Asia.

There are limited data for greenhouse gas (GHG) emissions from smallholder agricultural systems in tropical peatlands, with data for non-CO2 emissions from human-influenced tropical peatlands particularly scarce. The aim of this study was to quantify soil CH4 and N2 O fluxes from smallholder agricultural systems on tropical peatlands in Southeast Asia and assess their environmental controls. The study was carried out in four regions in Malaysia and Indonesia. CH4 and N2 O fluxes and environmental parameters were measured in cropland, oil palm plantation, tree plantation and forest. Annual CH4 emissions (in kg CH4 ha-1 year-1 ) were: 70.7 ± 29.5, 2.1 ± 1.2, 2.1 ± 0.6 and 6.2 ± 1.9 at the forest, tree plantation, oil palm and cropland land-use classes, respectively. Annual N2 O emissions (in kg N2 O ha-1 year-1 ) were: 6.5 ± 2.8, 3.2 ± 1.2, 21.9 ± 11.4 and 33.6 ± 7.3 in the same order as above, respectively. Annual CH4 emissions were strongly determined by water table depth (WTD) and increased exponentially when annual WTD was above -25 cm. In contrast, annual N2 O emissions were strongly correlated with mean total dissolved nitrogen (TDN) in soil water, following a sigmoidal relationship, up to an apparent threshold of 10 mg N L-1 beyond which TDN seemingly ceased to be limiting for N2 O production. The new emissions data for CH4 and N2 O presented here should help to develop more robust country level 'emission factors' for the quantification of national GHG inventory reporting. The impact of TDN on N2 O emissions suggests that soil nutrient status strongly impacts emissions, and therefore, policies which reduce N-fertilisation inputs might contribute to emissions mitigation from agricultural peat landscapes. However, the most important policy intervention for reducing emissions is one that reduces the conversion of peat swamp forest to agriculture on peatlands in the first place.

Global intercompany assessment of ICIEF platform comparability for the characterization of therapeutic proteins.

An international team spanning 19 sites across 18 biopharmaceutical and in vitro diagnostics companies in the United States, Europe, and China, along with one regulatory agency, was formed to compare the precision and robustness of imaged CIEF (ICIEF) for the charge heterogeneity analysis of the National Institute of Standards and Technology (NIST) mAb and a rhPD-L1-Fc fusion protein on the iCE3 and the Maurice instruments. This information has been requested to help companies better understand how these instruments compare and how to transition ICIEF methods from iCE3 to the Maurice instrument. The different laboratories performed ICIEF on the NIST mAb and rhPD-L1-Fc with both the iCE3 and Maurice using analytical methods specifically developed for each of the molecules. After processing the electropherograms, statistical evaluation of the data was performed to determine consistencies within and between laboratory and outlying information. The apparent isoelectric point (pI) data generated, based on two-point calibration, for the main isoform of the NIST mAb showed high precision between laboratories, with RSD values of less than 0.3% on both instruments. The SDs for the NIST mAb and the rhPD-L1-Fc charged variants percent peak area values for both instruments are less than 1.02% across different laboratories. These results validate the appropriate use of both the iCE3 and Maurice for ICIEF in the biopharmaceutical industry in support of process development and regulatory submissions of biotherapeutic molecules. Further, the data comparability between the iCE3 and Maurice illustrates that the Maurice platform is a next-generation replacement for the iCE3 that provides comparable data.

Sedentary time and its association with risk of cardiovascular diseases in adults: an updated systematic review and meta-analysis of observational studies.

BACKGROUND: Epidemiological studies assessing the association between sedentary time and cardiovascular diseases (CVD) risks have been published at a rapid pace in recent years, which makes the periodic review of knowledge essential. Furthermore, much of the early and ongoing work used screen time as a marker of total sedentary time, which may weaken the association between sedentary time and CVD risks. OBJECTIVE: To update evidence on CVD risks associated with different types of sedentary time, especially total sedentary time and screen time, and to explore as a marker of total sedentary time, whether screen time had similar CVD risks with total sedentary time. METHODS: PRISMA guideline was followed for the performing and reporting of this systematic review and meta-analysis. Three independent researchers searched eight electronic databases and two clinical trial registries for all studies published between January 2015 and December 2021 that assessed the association between sedentary time and CVD risks in adults. A standardized form was used for data extraction and collection. Wilmot and colleagues' modified tool was used for quality assessment. The categorical association was assessed by comparing the pooled effect sizes for CVD risks associated with the highest and the lowest sedentary time categories across included studies. Stata 16.0 and Review Manager 5.3 were used for all statistical analyses, P ≤ 0.05 was considered as statistically significant. RESULTS: Seventeen prospective cohort studies and two cross-sectional studies with 145,1730 participants and over 48,668 CVD cases and deaths were included. Two included studies measured sedentary time with the accelerometer, 16 studies with self-reported questions, and one study with both the accelerometer and self-reported questions. CVD outcomes were self-reported in two included studies and objectively adjudicated through medical records or death certifications in 17 studies. Compared with the lowest total sedentary time category (median duration, 2.75 h/d), participants in the highest category (median duration, 10.5 h/d) had an increased risk of CVD morbidity (pooled RR, 1.24; 95% CI, 1.21-1.27). Compared with the lowest total sedentary time category (median duration, 2.98 h/d), participants in the highest category (median duration, 10.2 h/d) had an increased risk of CVD mortality (pooled HR, 1.29; 95% CI, 1.13-1.47). The association between screen time and CVD risks was similar to total sedentary time with the cut-off point of 5-6 h/d. The associations between occupational sitting time, leisure sedentary time, and CVD risks stayed inconclusive. CONCLUSION: Total sedentary time and screen time are both associated with cardiovascular health. As a marker of total sedentary time, screen time over 5-6 h/d had similar CVD risks with total sedentary time over 10-11 h/d.

Anatomical and Pathological Observation and Analysis of SARS and COVID-19: Microthrombosis Is the Main Cause of Death.

The spread of the coronavirus (SARS-CoV-2, COVID-19 for short) has caused a large number of deaths around the world. We summarized the data reported in the past few months and emphasized that the main causes of death of COVID-19 patients are DAD (Diffuse Alveolar Damage) and DIC (Disseminated intravascular coagulation). Microthrombosis is a prominent clinical feature of COVID-19, and 91.3% of dead patients had microthrombosis.Endothelial damage caused by SARS-CoV-2 cell invasion and subsequent host response disorders involving inflammation and coagulation pathways play a key role in the progression of severe COVID-19. Microvascular thrombosis may lead to microcirculation disorders and multiple organ failure lead to death.The characteristic pathological changes of DAD include alveolar epithelial and vascular endothelial injury, increased alveolar membrane permeability, large numbers of neutrophil infiltration, alveolar hyaline membrane formation, and hypoxemia and respiratory distress as the main clinical manifestations. DAD leads to ARDS in COVID-19 patients. DIC is a syndrome characterized by the activation of systemic intravascular coagulation, which leads to extensive fibrin deposition in the blood. Its occurrence and development begin with the expression of tissue factor and interact with physiological anticoagulation pathways. The down-regulation of fibrin and the impaired fibrinolysis together lead to extensive fibrin deposition.DIC is described as a decrease in the number of platelets and an increase in fibrin degradation products, such as D-dimer and low fibrinogen. The formation of microthrombus leads to the disturbance of microcirculation, which in turn leads to the death of the patient. However, the best prevention and treatment of COVID-19 microthrombosis is still uncertain.This review discusses the latest findings of basic and clinical research on COVID-19-related microthrombosis, and then we proposed the theory of microcirculation perfusion bundle therapy to explore effective methods for preventing and treating COVID-19-related microthrombosis. Further research is urgently needed to clarify how SARS-CoV-2 infection causes thrombotic complications, and how it affects the course and severity of the disease. To cultivate a more comprehensive understanding of the underlying mechanism of this disease. Raise awareness of the importance of preventing and treating microthrombosis in patients with COVID-19.

Population pharmacokinetic and optimization of polymyxin B dosing in adult patients with various renal functions.

AIMS: Current FDA-approved label recommends that the dosage of polymyxin B should be adjusted according to renal function. However, the correlation between polymyxin B pharmacokinetics (PK) and creatinine clearance (CrCL) is poor. This study aimed to develop a population PK model of polymyxin B in adult patients with various renal functions and to identify a dosing strategy. METHODS: A retrospective PK study was performed in 32 adult patients with various renal function. Nonlinear mixed effects modelling was applied to build a population PK model of polymyxin B followed by Monte Carlo simulations which designed polymyxin B dosing regimens across various renal function. RESULTS: Polymyxin B PK analyses included 112 polymyxin B concentrations at steady state from 32 adult patients, in which 71.9% of them were critically ill. In the final PK model, CrCL was the significant covariate on CL (typical value 1.59 L/h; between-subject variability 13%). The mean (SD) individual empirical Bayesian estimate of CL was 1.75 (0.43) L/h. In addition, a new dosing strategy combining the PK/pharmacodynamic (PD) targets and Monte Carlo simulation indicated that the reduction of polymyxin B dose in patients with renal insufficiency improved the probability of achieving optimal exposure. For severe infections caused by organisms with minimum inhibitory concentration (MIC) ≥ 2 mg/L, a high daily dose of polymyxin B might be possible for bacterial eradication, but the risk of nephrotoxicity is increased. CONCLUSIONS: Renal function plays a significant role in polymyxin B PK, and the dose of polymyxin B should be adjusted according to CrCL in patients with renal insufficiency.

Association of FIB-4 index and clinical outcomes in critically ill patients with acute kidney injury: a cohort study.

BACKGROUND: The relationship between fibrosis-4 (FIB-4) index and clinical outcomes in patients with acute kidney injury (AKI) is unclear. We aimed to investigate the association between FIB-4 index and all-cause mortality in critically ill patients with AKI. METHODS: We used data from the Multiparameter Intelligent Monitoring in Intensive Care III (MIMIC-III) database (v1.4). The FIB-4 score was calculated using the existing formulas. logistic regression model, and Cox proportional hazards model were used to assessed the relationship between the FIB-4 index and in-hospital,28-day and 90-day mortality, respectively. RESULTS: A total of 3592 patients with AKI included in the data analysis. 395 (10.99%) patients died during hospitalization and 458 (12.74%) patients died in 28-day. During the 90-day follow-up, 893 (22.54%) patients were dead. An elevated FIB-4 value was significantly associated with increased in-hospital mortality when used as a continuous variable (odds ratio [OR] 1.183, 95% confidence interval [CI] 1.072-1.305, P = 0.002) and as a quartile variable (OR of Q2 to Q4 1.216-1.744, with Q1 as reference). FIB-4 was positively associated with 28-day mortality of AKI patients with hazard ratio (HR) of 1.097 (95% CI 1.008, 1.194) and 1.098 (95% 1.032, 1.167) for 90-day mortality, respectively. CONCLUSION: This study demonstrated the FIB-4 index is associated with clinical outcomes in critically ill patients with acute kidney injury.

The impact of the COVID-19 pandemic on the mental health of young people: A comparison between China and the United Kingdom.

PURPOSE: As COVID-19 spreads globally and affects people's health, there are concerns that the pandemic and control policies may have psychological effects on young people (age from 17 to 35 years). This psychological impact might vary in different countries, and thus we compared the prevalence of self-reported psychological distress, loneliness and posttraumatic stress symptoms (PTSS) among young people in the United Kingdom (UK) and China at the beginning of the COVID-19 pandemic. METHODS: Data of this study came from two sources. One source was the first wave of COVID-19 study in Understanding Society, a special wave of the UK household longitudinal study, which provided the high-quality, national-wide representative panel data. The sample comprised 1054 young people. The other source was an online survey on the mental health of 1003 young people from Shanghai, a highly developed area in China. The questionnaire included questions on the prevalence of common mental disorders (cut-off score ≥ 4), loneliness and potential PTSS (cut-off ≥ 33). Univariable analyses were conducted to test the differences in the self-reported prevalence of psychological distress and loneliness between the two groups. Multivariable logistic regression analyses were run to explore the predictors of psychological distress and loneliness among all the young people from England and Shanghai. RESULTS: Among the samples with self-reported psychological distress, the UK sample accounted for 34.4% (n=1054) and the Chinese sample accounted for 14.1% (n=1003). The difference between the two groups was statistically significant (p < 0.001). Additionally, 57.1% of people in the UK and 46.7% in China reported that they sometimes or often felt lonely, of which the difference is statistically significant (p < 0.001). Regression analysis of the entire samples showed that nationality, gender, psychotherapy and loneliness were significant predictors of 12-item General Health Questionnaire scores, while the variables of age and living alone were not. Significant predictors of self-reported loneliness were the nationality, gender, age, living alone and psychotherapy. In China, 123 (12.3%) young people, 49 men (11.3%) and 74 women (13.0%), met the criteria of PTSS symptoms (cut-off scores ≥ 33). These scores were only collected in China. CONCLUSION: This evidence suggests that mental health and loneliness reported by young people were lower in China than that in the UK during the studied period. More research is needed to understand these differences. If the differential negative psychological impacts are confirmed, country-specific measures of prevention and intervention should be adopted to improve the mental health of young people under the ongoing impact of the pandemic.

[A review on the effect of Claudin-18 on bronchopulmonary dysplasia in preterm infants].

Bronchopulmonary dysplasia (BPD) has the main manifestations of pulmonary edema in the early stage and characteristic alveolar obstruction and microvascular dysplasia in the late stage, which may be caused by structural and functional destruction of the lung epithelial barrier. The Claudin family is the main component of tight junction and plays an important role in regulating the permeability of paracellular ions and solutes. Claudin-18 is the only known tight junction protein solely expressed in the lung. The lack of Claudin-18 can lead to barrier dysfunction and impaired alveolar development, and the knockout of Claudin-18 can cause characteristic histopathological changes of BPD. This article elaborates on the important role of Claudin-18 in the development and progression of BPD from the aspects of lung epithelial permeability, alveolar development, and progenitor cell homeostasis, so as to provide new ideas for the pathogenesis and clinical treatment of BPD.

Left-sided accessory pathways successfully ablated from the aortomitral continuity region: distinctive atrial activation patterns and anatomic concerns.

AIMS: Accessory pathways (APs) successfully ablated at the aortomitral continuity (AMC) were sporadically reported but relevant data are very limited. We aimed to describe the electrophysiological characteristics of AMC-AP and the related anatomy. METHODS AND RESULTS: This study involved eight (male/female = 3/5, mean age 42.6 ± 10.5 years) patients with left-sided AP successfully ablated in the AMC region. The retrograde atrial activation sequence was analysed and compared via recordings at the His-bundle (HB), coronary sinus (CS), and roving catheter during tachycardia, and the peak of QRS from the same cardiac circle used as time reference. Of the eight patients, two received prior ablations. During tachycardia, the activation time at the proximal CS (CSp), lateral CS (CSl), and HB region averaged 120 ± 26 ms, 124 ± 29 ms, and 117 ± 21 ms following the reference, respectively (P = 0.86). The latest atrial activation was recorded in the posterior CS which averaged 135 ± 25 ms following the reference. Placing the ablation catheter to AMC via retrograde approach was attempted in all cases but stable positioning achieved in none. Via transseptal approach, the ablation catheter could be easily placed at the AMC and recorded the earliest retrograde atrial activations with 60 ± 27 ms earlier than the relatively 'earliest' CS/HB recordings, and ablation at this site successfully eliminated AP conduction. No patients had recovered AP conduction after at least 12-month follow-up. CONCLUSION: AMC-AP is featured by recording comparable retrograde atrial activation times at CSp, CSl, and HB with the latest recordings at the posterior CS. Stable placement and successful ablation in the AMC via retrograde aortic approach was difficult but can be achieved via transseptal approach.

Analysis of internal spermatic vein embolization through catheter versus laparoscopic high ligation in treatment of left varicocele.

OBJECTIVE: Varicocele is a common disease in young and middle-aged men. This study aims to compare the efficacy of internal spermatic vein embolization of left varicocele versus laparoscopic high ligation. METHODS: From January 2017 to September 2018, a total of 69 varicocele patients were admitted and given the opportunity to choose the treatment option. Among these, 26 patients were treated with sclerosing agent injection, while 43 patients underwent laparoscopic surgery. They were followed up for 12 months after surgery, and the technical success rate, recurrence rate, complication rate, cost, operative time, and hospitalization time with regard to these two methods were analyzed. RESULTS: All patients completed the medical procedures. There was no recurrence in patients in the sclerotherapy group during the follow-up period; however, the complication rate was 19.2%. Furthermore, the operative time, hospitalization time, and cost of treatment were 31.1 ± 11.1 min, 1.2 ± 0.49 days, and 9613.11 ± 895.97 Yuan, respectively. In the laparoscopic group, 9 patients underwent laparoscopic bilateral high ligation, while 34 patients received treatment on the left side alone. The recurrence rate of left varicocele was 4.7% and the complication rate was 44.2%. Furthermore, the operative time, hospitalization time, and treatment cost were 50.4 ± 14.48 min, 4.0 ± 2.02 days, and 10,948.29 ± 2547.00 Yuan, respectively. Moreover, there were statistically significant differences (P < 0.05) in operative time, hospitalization time, and treatment cost. Patients in the sclerotherapy group had an advantage with respect to the overall complication rate when compared with patients from the laparoscopic group (X2 = 4.448, P < 0.05), and there was a statistically significant difference in hydrocele (X2 = 4.555, P < 0.05). However, there was no significant difference in the recurrence rate between these two groups (X2 = 1.245, P > 0.05). CONCLUSION: Patients who underwent sclerotherapy showed a higher technical success rate, a lower recurrence rate, fewer complications, and shorter hospitalization time compared to those treated with laparoscopic ligation. Transcatheter sclerosing agent injection may be a preferable treatment option for patients with unilateral varicocele.

Recurrent Talaromyces marneffei Infection Presenting with Intestinal Obstruction in a Patient with Systemic Lupus Erythematosus.

Talaromyces marneffei is an important opportunistic pathogen mainly afflicting the HIV-infected patients, in rare instance, it could cause infection in non-HIV-infected individuals. We report a 51-year-old Chinese woman who, with histories of SLE for 14 years and disseminated talaromycosis for 4 years, occurred partial intestinal obstruction that was demonstrated to be caused by Talaromyces marneffei infection. The randomly amplified polymorphic DNA results of paraffin-embedded tissues from both the present episode and the previous infection suggested that the present infection was a recurrent. The patient was performed excision of involved intestine and treated with oral itraconazole at a daily dose of 400 mg for 3 months, leading to an excellent response. However, she died with unknown reason more than a year later. We also reviewed the literature on Talaromyces marneffei infection associated with SLE as well as intestinal talaromycosis alone.

[Cloning and functional characterization of farnesyl diphosphate synthase in Senecio scandens].

As a secondary metabolite, sesquiterpenes are not only have important functions in plant defense and signaling, but also play potential roles in basic materials for pharmaceuticals, cosmetic and flavor. As a traditional Chinese herbal medicine, Senecio scandens exhibits effects of anti-inflammatory and immunosuppressive, as well as invigorating the blood and removing extravasated blood. Over 600 sesquiterpenes with diverse structures were isolated from S. scandens and related species in the same genus. To characterize sesquiterpenes synthesis, two FPS genes(SsFPS1 and SsFPS2) were identified in S. scandens through transcriptomic analysis. Bioinformatic analysis showed that both SsFPSs have conserved motifs for FPS function. Both SsFPSs exhibited constitutive gene expression in S. scandens tissues and SsFPS2 accumulated higher transcript in leaves and roots than SsFPS1. Meanwhile consistent with constitutive sesquiterpene accumulation in S.scandens tissues, most of these sesquiterpenes were detected in leaves and roots more than stems and flowers. Recombinant expression through Escherichia coli metabolic engineering, SsFPS1 or SsFPS2 was co-transformed with ZmTPS11(maize ß-macrocarpene synthase) into BL21 competent cells. The results showed that the content of ß-macrocarpene was increased by co-transformation with SsFPSs. It is demonstrated that SsFPS1 and SsFPS2 catalyzed E,E-FPP formation and provided FPP precursor for downstream sesquiterpene synthases. Characterization of SsFPSs provided the foundation for the exploration of biosynthesis of sesquiterpenoid with diverse structures and potential pharmaceutical values in S.scandens, and provide an important theoretical basis for the development of S. scandens abundant resources.

Regulation of G6PD acetylation by SIRT2 and KAT9 modulates NADPH homeostasis and cell survival during oxidative stress.

Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme in the pentose phosphate pathway (PPP) and plays an essential role in the oxidative stress response by producing NADPH, the main intracellular reductant. G6PD deficiency is the most common human enzyme defect, affecting more than 400 million people worldwide. Here, we show that G6PD is negatively regulated by acetylation on lysine 403 (K403), an evolutionarily conserved residue. The K403 acetylated G6PD is incapable of forming active dimers and displays a complete loss of activity. Knockdown of G6PD sensitizes cells to oxidative stress, and re-expression of wild-type G6PD, but not the K403 acetylation mimetic mutant, rescues cells from oxidative injury. Moreover, we show that cells sense extracellular oxidative stimuli to decrease G6PD acetylation in a SIRT2-dependent manner. The SIRT2-mediated deacetylation and activation of G6PD stimulates PPP to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes. We also identified KAT9/ELP3 as a potential acetyltransferase of G6PD. Our study uncovers a previously unknown mechanism by which acetylation negatively regulates G6PD activity to maintain cellular NADPH homeostasis during oxidative stress.

Erratum to: In vivo enhancement of the MAGE-specific cellular immune response by a recombinant MAGE1-MAGE3-TBHSP70 tumor vaccine.

[This corrects the article DOI: 10.1186/s12935-016-0317-2.].

Prognostic value of platelet-to-lymphocyte ratios among critically ill patients with acute kidney injury.

BACKGROUND: Inflammation plays an important role in the initiation and progression of acute kidney injury (AKI). However, evidence regarding the prognostic effect of the platelet-to-lymphocyte ratio (PLR), a novel systemic inflammation marker, among patients with AKI is scarce. In this study, we investigated the value of the PLR in predicting the outcomes of critically ill patients with AKI. METHODS: Patient data were extracted from the Multiparameter Intelligent Monitoring in Intensive Care Database III version 1.3. PLR cutoff values were determined using smooth curve fitting or quintiles and were used to categorize the subjects into groups. The clinical outcomes were 30-day and 90-day mortality in the intensive care unit (ICU). Cox proportional hazards models were used to evaluate the association between the PLR and survival. RESULTS: A total of 10,859 ICU patients with AKI were enrolled. A total of 2277 thirty-day and 3112 ninety-day deaths occurred. A U-shaped relationship was observed between the PLR and both 90-day and 30-day mortality, with the lowest risk being at values ranging from 90 to 311. The adjusted HR (95% CI) values for 90-day mortality given risk values < 90 and > 311 were 1.25 (1.12-1.39) and 1.19 (1.08-1.31), respectively. Similar trends were observed for 30-day mortality or when quintiles were used to group patients according to the PLR. Statistically significant interactions were found between the PLR and both age and heart rate. Younger patients (aged < 65 years) and those with more rapid heart rates (≥89.4 beats per minute) tended to have poorer prognoses only when the PLR was < 90, whereas older patients (aged ≥ 65 years) and those with slower heart rates (<89.4 beats per minute) had higher risk only when the PLR was > 311 (P < 0.001 for age and P < 0.001 for heart rate). CONCLUSIONS: The preoperative PLR was associated in a U-shaped pattern with survival among patients with AKI. The PLR appears to be a novel, independent prognostic marker of outcomes in critically ill patients with AKI.

In vivo enhancement of the MAGE-specific cellular immune response by a recombinant MAGE1-MAGE3-TBHSP70 tumor vaccine.

BACKGROUND: Since cytotoxic T cell (CTL) response is the major cellular type in attacking tumor cells, most immunotherapy targets to manipulate the CTL response. Immunotherapies targeting melanoma-specific antigens (MAGEs), a group of tumor-specific shared antigen, have shown to be promising. Our previous study has shown that MAGE1/TBHSP70 and MAGE3/TBHSP70 could induce a robust immune response against B-16 melanoma cells in C57BL/6 mice. In this study, we used an animal model to further demonstrate MAGEs as a potential immunotherapy target for tumorigenesis in vivo. METHODS: In the current study, we developed a MAGE1/MAGE3/TBHSP70 recombinant protein vaccine and evaluated its protective efficacy against tumor development by challenge vaccine-immunized mice with MAGE-expressing human tumor cell lines in a Hu-PBL-SCID mouse model. The cellular immune reactions were monitored by ELISPOT and cytotoxicity assays. RESULTS: Splenocytes isolated from vaccine-immunized mice presented potent cytokine secretion capacity and CTL-specific cytotoxic. Vaccine-immunized mice had a significant tumor regression and prolonged survival compared with controls (both p < 0.05). In vitro, rMAGE1-MAGE3-TBHSP70 showed a potent tumor-antigen-specific immune response in both hepatocellular carcinoma and pulmonary carcinoma cell lines. CONCLUSION: This newly-developed recombinant protein vaccine may serve as a new immunotherapy for cancer.

Sensitivity of genotypically diverse rice varieties to radiation and the related changes to antioxidant enzyme activities.

PURPOSE: Radiation mutagenesis, which typically involves gamma rays, is important for generating new rice germplasm resources. Determining the appropriate radiation dose range is critical for the success of radiation mutagenesis. Clarifying the sensitivity and tolerance of genotypically diverse rice varieties to gamma irradiation as well as the radiation-induced changes to reactive oxygen species (ROS) generation and antioxidant enzyme activities is crucial for increasing the utility of radiation mutagenesis in rice breeding programs. MATERIALS AND METHODS: The seeds of the following four rice varieties with different genotypes were used as test materials: indica Zhe 1613, glutinous indica Zhe 1708, japonica Zhejing 100, and glutinous japonica Zhenuo 65. Additionally,60Co was used as the source of gamma rays. The rice seeds were irradiated with 14 doses (0, 150, 200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, and 750 Gy). Non-irradiated seeds were used as the control. The seedling survival rate for each variety was recorded at 3, 7, 14, and 28 days after sowing. Moreover, the median lethal dose (LD50) and critical dose (LD40) were calculated according to the seedling survival rates at 28 days after sowing. The seedling superoxide anion (O2•-), hydrogen peroxide (H2O2), and malondialdehyde (MDA) contents and the superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), and ascorbate peroxidase (APX) activities were analyzed at 7 days after sowing. RESULTS: As the radiation dose increased, the seedling survival rate decreased. The seedling survival rate also decreased significantly as the number of days after sowing increased. Among the rice genotypes, the rank-order of the radiation tolerance was as follows: indica Zhe 1613 > glutinous indica Zhe 1708 > japonica Zhejing 100 > glutinous japonica Zhenuo 65. The LD50 values were 426.7 Gy for Zhe 1613, 329.2 Gy for Zhe 1708, 318.3 Gy for Zhejing 100, and 316.6 Gy for Zhenuo 65. Increases in the radiation dose resulted in significant increases in the seedling O2•- and H2O2 contents, but only up to a certain point. Further increases in the radiation dose caused the seedling O2•- and H2O2 contents to decrease. The H2O2 content for each variety peaked when the radiation dose was very close to the LD50. We propose that the radiation dose associated with the highest H2O2 content (±50 Gy) should be used as the recommended dose for the gamma irradiation of rice. The radiation dose that resulted in peak seedling O2•- contents in the analyzed rice varieties was very close to the LD40. In all rice varieties, the MDA content increased as the radiation dose increased. The SOD, CAT, POD, and APX activities increased as the radiation dose increased within a certain range (less than 600 Gy for Zhe 1613 and 400 Gy for the other varieties), but there were slight differences among the rice varieties. CONCLUSIONS: Genotypically diverse rice varieties vary regarding their sensitivity to gamma irradiation. Our findings suggest that ROS generation and antioxidant enzyme activities are important factors associated with the radiation mutagenesis of rice. The close relationship between the activities of key antioxidant enzymes, such as SOD, POD, APX, and CAT, and the LD50 and LD40 may be exploited to enhance radiation mutagenesis through the use of plant growth regulators.

Simvastatin ameliorates synaptic plasticity impairment in chronic mild stress-induced depressed mice by modulating hippocampal NMDA receptor.

BACKGROUND: In our previous study, we showed simvastatin exerts an antidepressant effect and inhibits neuroinflammation. Given the role of synaptic impairment in depression development, we investigate the effect of simvastatin on synaptic plasticity in depression and the related mechanisms. METHODS: Electrophysiological analysis, Golgi staining, and transmission electron microscope were performed to analyze the effect of simvastatin on synaptic impairment in depression. In addition, the localization and reactivity of N-methyl-D-aspartate receptor (NMDAR) subunits and the downstream signaling were investigated to explore the mechanism of simvastatin's effect on synaptic plasticity. RESULTS: Simvastatin ameliorated the reduction of the magnitude of long-term potentiation (LTP) in Schaffer collateral-CA1, restored hippocampal dendritic spine density loss, improved the number of spine synapses, reversed the reduction in BrdU-positive cells in chronic mild stress (CMS)-induced depressed mice, and ameliorated NMDA-induced neurotoxicity in hippocampal neurons. Dysfunction of NMDAR activity in the hippocampus is associated with depression. Simvastatin treatment reversed the surface expression and phosphorylation changes of NMDAR subunits in NMDA-treated hippocampal neurons and depressed mice. In addition, simvastatin further increased the levels of mature BDNF, activating TrkB-Akt-mTOR signaling, which is critical for synaptic plasticity. CONCLUSIONS: These findings suggest that simvastatin can improve the dysfunction of NMDAR and ameliorate hippocampal synaptic plasticity impairment in depressed mice.