An HPLC-MS/MS method for determination of sulbactam in human plasma and its pharmacokinetic application in critically ill patients with augmented renal clearance.

OBJECTIVE: A simple, rapid, and specific method has been developed and validated to measure sulbactam in human plasma using high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). MATERIALS AND METHODS: The pharmacokinetic characteristics of sulbactam in critically ill patients with augmented renal clearance were investigated after the repeated administration of cefoperazone-sulbactam (3 g, q8, IV drip, combination ratio of 2 : 1). Sulbactam plasma concentration was determined using LC-MS/MS with tazobactam used as an internal standard (IS). RESULTS: The method was fully validated with a sensitivity of 0.20 µg/mL, the linear concentration was ranged from 0.20 to 30.0 µg/mL. The intra-batch precision (RSD%) was less than 4.9%, and the accuracy deviation (RE%) ranged from -9.9 to 1.0%; the inter-batch precision (RSD%) was less than 6.2%, and the accuracy deviation (RE%) ranged from -9.2% to 3.7%. The value of the mean matrix factor at the low and high quality control (QC) concentration was 96.8 and 101.0%, respectively. The extraction recovery for QCL and QCH of sulbactam were 92.5 and 87.5%,respectively. Plasma samples and clinical data were collected at 0 (pre dose), 0.25, 0.5, 1, 2, 3, 6, and 8 hours (post dose) from 11 critically ill patients. Pharmacokinetic parameters were determined by non-compartmental analysis (NCA) using Phoenix WinNonlin software. CONCLUSION: This method was successfully applied to study the pharmacokinetics of sulbactam for critically ill patients. The main pharmacokinetic parameters of sulbactam in augmented renal function and normal renal function groups were summarized as follows: half-life, 1.45 ± 0.66 and 1.72 ± 0.58 hours, area under the concentration-time curve from 0 to 8 hours, 59.1 ± 20.1 and 111.4 ± 23.2 µg × h/mL, drug plasma clearance at steady state, 18.9 ± 7.5 and 9.32 ± 2 .03 L/h, respectively. These results suggested that a higher dose of sulbactam should be used in critically ill patients with augmented renal clearance.

Effect of empirical antifungal treatment on mortality in non-neutropenic critically ill patients: a propensity-matched retrospective cohort study.

To evaluate the effect of empirical antifungal treatment (EAFT) on mortality in critically ill patients without invasive fungal infections (IFIs). This was a single-center propensity score-matched retrospective cohort study involving non-transplanted, non-neutropenic critically ill patients with risk factors for invasive candidiasis (IC) in the absence of IFIs. We compared all-cause hospital mortality and infection-attributable hospital mortality in patients who was given EAFT for suspected IC as the cohort group and those without any systemic antifungal agents as the control group. Among 640 eligible patients, 177 patients given EAFT and 177 control patients were included in the analyses. As compared with controls, EAFT was not associated with the lower risks of all-cause hospital mortality [odds ratio (OR), 0.911; 95% CI, 0.541-1.531; P = 0.724] or infection-attributable hospital mortality (OR, 1.149; 95% CI, 0.632-2.092; P = 0.648). EAFT showed no benefit of improvement of infection at discharge, duration of mechanical ventilation, and antibiotic-free days. However, the later initiation of EAFT was associated with higher risks of all-cause hospital mortality (OR, 1.039; 95% CI, 1.003 to 1.076; P = 0.034) and infection-attributable hospital mortality (OR, 1.046; 95% CI, 1.009 to 1.085; P = 0.015) in patients with suspected IC. This effect was also found in infection-attributable hospital mortality (OR, 1.042; 95% CI, 1.005 to 1.081; P = 0.027) in septic patients with suspected IC. EAFT failed to decrease hospital mortality in non-neutropenic critically ill patients without IFIs. The timing may be critical for EAFT to improve mortality in these patients with suspected IC. ChiCTR2000038811, registered on Oct 3, 2020.

Prenatal predictors in postpartum recovery for acute fatty liver of pregnancy: experiences at a tertiary referral center.

PURPOSE: The purpose of this study was to describe some prenatal characteristics and laboratory findings of acute fatty liver of pregnancy (AFLP) and provide the clinicians with reasonable predictors and expectation in postpartum recovery. METHODS: At a tertiary referral center 43 patients with AFLP were entered into this retrospective study in 5 years based on the Swansea criteria. Emergent cesarean sections were performed within 24 h, and the criteria of recovery after operation was based on a uniform standard. All of them were hospitalized and treated at the same department of obstetrics and maternal intensive care unit. RESULTS: Prenatally, all women with AFLP had elevated serum hepatic aminotransferase and serum bilirubin levels. Albumin level was decreased in 88 % women and hypoglycemia was documented in 56 % women. Plasma fibrinogen level of 93 % patients was less than 1.75 g/L and prothrombin time (PT) of 91 % was prolonged abnormally. The duration of recovery after delivery ranged from 5 to 20 days. Pearson correlation coefficient between duration of recovery and hyperbilirubinemia was 0.639 (P = 0.001). The levels of PT, plasma fibrinogen and platelet counts were also correlated with the recovery time (R = 0.459, P = 0.002; R = 0.427, P = 0.004; R = 0.435, P = 0.004). Elevated leukocytes, hypoglycaemia, hepatic aminotransferase and uric acid levels showed no value for predicting the prognosis of AFLP (P > 0.01). CONCLUSIONS: AFLP is a rare but serious complication in the third trimester. Prenatal serum bilirubin, PT, plasma fibrinogen levels and platelet counts are the predictors of postpartum recovery, but some Swansea diagnosis criteria do not have the same prognostic significance as others.

Comparative pharmacokinetics of polymyxin B in critically ill elderly patients with extensively drug-resistant gram-negative bacteria infections.

Introduction: Elderly patients are more prone to develop acute kidney injury during infections and polymyxin B (PMB)-associated nephrotoxicity than young patients. The differential response to PMB between the elderly and young critically ill patients is unknown. We aimed to assess PMB exposure in elderly patients compared with young critically ill patients, and to determine the covariates of PMB pharmacokinetics in critically ill patients. Methods: Seventeen elderly patients (age ≥ 65 years) and six young critically ill patients (age < 65 years) were enrolled. Six to eight blood samples were collected during the 12 h intervals after at least six doses of intravenous PMB in each patient. PMB plasma concentrations were quantified by high-performance liquid chromatography-tandem mass spectrometry. The primary outcome was PMB exposure as assessed by the area under the concentration-time curve over 24 h at steady state (AUCss, 0-24 h). Results and Discussion: The elderly group had lower total body weight (TBW) and higher Charlson comorbidity scores than young group. Neither AUCss, 0-24 h nor normalized AUCss, 0-24 h (adjusting AUC for the daily dose in mg/kg of TBW) was significantly different between the elderly group and young group. The half-life time was longer in the elderly patients than in young patients (11.21 vs 6.56 h respectively, p = 0.003). Age and TBW were the covariates of half-life time (r = 0.415, p = 0.049 and r = -0.489, p = 0.018, respectively). TBW was the covariate of clearance (r = 0.527, p = 0.010) and AUCss, 0-24 h (r = -0.414, p = 0.049). Patients with AUCss, 0-24 h ≥ 100 mg·h/L had higher baseline serum creatinine levels and lower TBW than patients with AUCss, 0-24 h < 50 mg·h/L or patients with AUCss, 0-24 h 50-100 mg·h/L. The PMB exposures were comparable in elderly and young critically ill patients. High baseline serum creatinine levels and low TBW was associated with PMB overdose. Trial registration: ChiCTR2300073896 retrospectively registered on 25 July 2023.

Effectiveness of combining plasma exchange with continuous hemodiafiltration on acute Fatty liver of pregnancy complicated by multiple organ dysfunction.

Acute fatty liver of pregnancy (AFLP) is a rare disease of progressive hepatic insufficiency and secondary systemic complications that induce significant maternal risk. The application of combining plasma exchange (PE) and continuous hemodiafiltration (CHDF) is a novel concept for patients with AFLP. Since 2002, we have utilized the combination of PE with CHDF as adjunctive medical therapy for 11 AFLP patients with multiple organ dysfunction. Before PE and CHDF initiation, four patients had signs and symptoms of encephalopathy, four required ventilatory support, and all 11 were developing liver failure, significant renal compromise, and coagulopathy. PE combined with CHDF for patients was initiated a mean of 2 days postpartum (range, days 0-3). Daily or every other day PE combined with CHDF was undertaken on two to eight occasions for each of the 11 patients. Ten patients responded with composite clinical and laboratory improvement and were discharged to the ward, then cured and discharged from hospital; one patient died of septic shock. Average duration of hospitalization was 17 days (range, days 9-38) from time of admission to discharge; the average duration of intensive care unit was 10 days (range, days 4-23). No significant PE- and CHDF-related complications occurred. These results indicate that combing PE and CHDF in a series-parallel circuit is an effective and safe treatment for patients with severe AFLP. This finding may have important implications for the development of an effective treatment for patients with AFLP suffering multiple organ dysfunction.

[Adenovirus mediated N19RhoA gene transfer attenuates neointimal formation in rats after carotid artery balloon injury].

OBJECTIVE: To investigate the role of small G-protein RhoA in neointimal formation following rat carotid artery balloon injury and related mechanisms. METHODS: Male 3-4-month-old Sprague-Dawley rats were used in the present study (10 rats per group). Group A: control; Group B: carotid artery balloon injury; Group C: injury + Ad-CMV-eGFP + Pluronic F-127; Group D: injury + Ad-CMV-N19RhoA-eGFP + Pluronic F-127; Group E: non injury + Ad-CMV-eGFP + Pluronic F-127. Perivascular gene transfer of an adenovirus co-expressing N19RhoA was performed to rat carotid artery following balloon injury and the effect on neointimal formation and the expressions of PCNA and α-SM-actin examined. Rats were killed after 14 days. RESULTS: The protein expression of RhoA in group B was significantly higher than in group A (P = 0.001), and the positive cells rate of PCNA and α-SM-actin which were assessed by immunohistochemistry in group C (45.2% and 75.6%) was significantly higher than in group D (28.4% and 51.9%, all P < 0.01). The area of neointima was significantly smaller [(0.14 ± 0.08) mm(2) vs. (0.23 ± 0.10) mm(2), P < 0.01], the luminal area was significantly larger [(0.47 ± 0.11) mm(2) vs. (0.31 ± 0.06) mm(2), P < 0.01] in group D than in group C. CONCLUSION: Gene transfer of N19RhoA attenuates neointimal formation after balloon injury in rat carotid arteries possibly related to the modulating capacities of small G-protein RhoA on the proliferation, phenotypic differentiation and migration of vascular adventitial fibroblasts.

[The effects of joint administration of 6% hydroxyethyl starch 130/0.4 and high-volume hemofiltration on patients with acute lung injury and acute kidney injury].

OBJECTIVE: To evaluate the effects of administration of 6% hydroxyethyl starch (6% HES 130/0.4, voluven) in combination with high volume hemofiltration (HVHF) in patients with ALI and AKI. METHODS: One hundred and eight patients with acute lung injury (ALI) and acute kidney injury (AKI) were enrolled from Department of Intensive Care Unit (ICU) of the provincial Hospital Affiliated to Shandong University between August 2006 and May 2011. The patients were randomly divided into two groups A (n = 68) and B (n = 40) to receive voluven (i.v., for volume resuscitation) and voluven+HVHF for 72 hours. The arterial blood lactate concentration (Lac), high sensitivity C-reactive protein (hs-CRP) serum concentration, pulmonary function index alveolar-arterial oxygen pressure difference [P(A-a)DO2] and oxygenation index (OI), as well as kidney function index serum cystatin C (Cyst C) and serum creatinine clearance rate (CCr) were measured at the time of admission and 72 hours after the treatment for statistical analysis. RESULTS: In comparison with group A, group B had significantly (all P < 0.01) lower mean value in the level of arterial Lac (mmol/L: 1.7 ± 0.7 vs. 2.7 ± 1.5), serum hs-CRP (mg/L: 35.8 ± 18.8 vs. 99.5 ± 20.4), P(A-a)DO2 (mm Hg, 1 mm Hg=0.133 kPa: 115.5 ± 23.1 vs. 155.4 ± 27.4), Cyst C (mg/L: 2.06 ± 1.12 vs. 3.95 ± 2.06) and significantly higher (both P < 0.01) mean value of OI (mm Hg: 295.2 ± 38.8 vs. 239.5 ± 32.7) and CCr (ml/min: 108.71 ± 31.33 vs. 90.21 ± 30.35) 72 hours after treatment. The mortality rate of group B was significantly lower than group A [10.00%(4/40) vs. 29.41%(20/68), P < 0.05] 7 days after the admission. CONCLUSION: 6% HES 130/0.4 in combination with HVHF could improve the lung and kidney function of the patients with ALI and AKI, prevent the development of multiple organ dysfunction syndrome (MODS), therefore improve the survival rate of these patients.

Sex Differences on Clinical Characteristics, Severity, and Mortality in Adult Patients With COVID-19: A Multicentre Retrospective Study.

Background: Coronavirus disease-2019 (COVID-19) epidemic is spreading globally. Sex differences in the severity and mortality of COVID-19 emerged. This study aims to describe the impact of sex on outcomes in COVOD-19 with a special focus on the effect of estrogen. Methods: We performed a retrospective cohort study which included 413 patients (230 males and 183 females) with COVID-19 from three designated hospitals in China with a follow up time from January 31, 2020, to April 17, 2020. Women over 55 were considered as postmenopausal patients according to the previous epidemiological data from China. The interaction between age and sex on in-hospital mortality was determined through Cox regression analysis. In addition, multivariate Cox regression models were performed to explore risk factors associated with in-hospital mortality of COVID-19. Results: Age and sex had significant interaction for the in-hospital mortality (P < 0.001). Multivariate Cox regression showed that age (HR 1.041, 95% CI 1.009-1.073, P = 0.012), male sex (HR 2.033, 95% CI 1.007-2.098, P = 0.010), the interaction between age and sex (HR 1.118, 95% CI 1.003-1.232, P = 0.018), and comorbidities (HR 9.845, 95% CI 2.280-42.520, P = 0.002) were independently associated with in-hospital mortality of COVID-19 patients. In this multicentre study, female experienced a lower fatality for COVID-19 than male (4.4 vs. 10.0%, P = 0.031). Interestingly, stratification by age group revealed no difference in-hospital mortality was noted in women under 55 compared with women over 55 (3.8 vs. 5.2%, P = 0.144), as well as in women under 55 compared with the same age men (3.8 vs. 4.0%, P = 0.918). However, there was significantly difference in women over 55 with men of the same age group (5.2 vs. 21.0%, P = 0.007). Compared with male patients, female patients had higher lymphocyte (P < 0.001) and high-density lipoprotein (P < 0.001), lower high sensitive c reaction protein level (P < 0.001), and lower incidence rate of acute cardiac injury (6.6 vs. 13.5%, P = 0.022). Conclusion: Male sex is an independent risk factor for COVID-19 in-hospital mortality. Although female mortality in COVID-19 is lower than male, it might not be directly related to the effect of estrogen. Further study is warranted to identify the sex difference in COVID-19 and mechanisms involved.

Effects of clopidogrel on vascular proliferation and apoptosis in an atherosclerotic rabbit model.

Inflammation, vascular proliferation. and apoptosis contribute to the process of atherosclerosis. Clopidogrel has been used to treat atherosclerosis; however, the mechanism is not entirely known. Compared with those of atorvastatin, we determined effects of clopidogrel on inflammatory factors, vascular proliferation, and apoptosis in an atherosclerosis rabbit model. New Zealand white rabbits were fed a normal diet or a high cholesterol diet for 7 weeks. The right iliac artery of animals except those in the negative control group were balloon-injured 1 week after initiation of the diet, and groups of animals were treated with clopidogrel (4 mg/kg per day), atorvastatin (2.5 mg/kg per day), or placebo (positive control group) for 6 weeks. We found that the placebo group had significant progression of atherosclerosis compared with the negative control group. In contrast, clopidogrel- or atorvastatin-treated rabbits showed a significant reduction in progression of atherosclerosis, including a low expression of high sensitivity C-reactive protein and platelet-derived growth factor, a reduced intima thickness, and reduced ratio of bcl-2/bax in the vascular wall. These results suggest that clopidogrel can retard the progression of established lesions that is related to inhibiting inflammation, cell proliferation, and promotion of cell apoptosis.

[The role of p38 mitogen-activated protein kinase in interleukin-6 induction by lipopolysaccharide in vascular smooth muscle cells].

OBJECTIVE: To investigate the regulation mechanism of p38 mitogen-activated protein kinase (p38MAPK) in interleukin-6 (IL-6) expression of vascular smooth muscle cell (VSMC) induced by lipopolysaccharide (LPS). METHODS: Rat VSMCs were divided into LPS group, SB203580+LPS group, SB203580 group and control group. LPS group was treated with 100 microg/L LPS for 0, 3, 6, 12, 24 hours, SB203580+LPS group was first treated with 10 micromol/L SB203580 for 2 hours and then exposed to 100 microg/L LPS for 0, 3, 6, 12, 24 hours, SB203580 group was pretreated with 10 micromol/L SB203580 for 2 hours. The level of IL-6 mRNA was determined by real-time polymerase chain reaction (PCR) and IL-6 secretion in the culture medium was measured by enzyme linked immunosorbent assay (ELISA) at different time points. RESULTS: The expression of IL-6 mRNA and the release of IL-6 were increased significantly in VSMC as early as 3 hours after being treated with LPS [mRNA: (21.3+/-3.2)x10(4), protein: (296.2+/-19.6) ng/L], peaked in 12 hours [mRNA: (131.4+/-11.2)x10(4), protein: (897.7+/-34.0) ng/L], and the elevation persisted up to 24 hours after treatment [mRNA: (15.3+/-4.7)x10(4), protein: (194.3+/-24.0) ng/L] compared with control group [mRNA: (9.4+/-1.9)x10(4), protein: (29.4+/-4.4) ng/L, all P<0.05]. On the other hand, the expression of IL-6 was significantly suppressed by p38MAPK inhibitor SB203580 at 3, 6, 12 hours [mRNA: (15.4+/-3.6)x10(4), (43.2+/-6.6)x10(4), (56.2+/-5.5)x10(4), protein: (180.3+/-23.6), (432.2+/-56.8), (546.2+/-57.9) ng/L, all P<0.05]. CONCLUSION: The release of IL-6 and the expression of IL-6 mRNA was increased significantly in LPS-challenged VSMC; however, the induction of IL-6 was significantly suppressed by p38MAPK inhibitor. p38MAPK may play an important role in the release of IL-6 induced by LPS.

[Study the effects of high-volume hemofiltration and fluid resuscitation on removing blood lactic acid and pro-inflammatory cytokines in patients with refractory septic shock].

OBJECTIVE: To evaluate the effects of high-volume hemofiltration (HVHF) and fluid resuscitation on the levels of arterial lactate and inflammatory cytokines, the acute physiology and chronic health evaluation II (APACHE II) score, and sepsis-related organ failure assessment (SOFA) score in patients with refractory septic shock and multiple organ dysfunction syndrome (MODS). METHODS: Eighty-nine patients with refractory septic shock and MODS undergoing HVHF, fluid resuscitation were included in the trial, and they were randomly divided into fluid resuscitation group (group A, 41 cases) and HVHF and fluid resuscitation group (group B, 48 cases). The changes in arterial lactate, lactate clearance rate, interleukin-6 (IL-6), procalcitonin (PCT), high sensitivity C-reactive protein (hs-CRP), APACHE II score and SOFA score in patients with refractory septic shock and MODS were determined before and after the treatment. RESULTS: (1) The arterial lactate clearance rate after treatment in both groups was elevated gradually. The level of lactate clearance rate in group B at 6, 12, 24 hours [(18.8+/-10.3)%, (31.6+/-11.4)%, (39.2+/-16.4)%] were higher than that of group A, respectively [(10.7+/-7.5)%, (14.7+/-10.3)%, (16.5+/-10.2)%, P < 0.05 or P < 0.01]. (2) The levels of pro-inflammatory cytokine IL-6, PCT and hs-CRP were reduced gradually after treatment in both groups. After treatment, the serum concentration of IL-6, PCT and hs-CRP levels in group B were reduced significantly more than that in group A at 1 day and 3 days (P < 0.05 or P < 0.01). (3) The APACHE II and SOFA scores in both groups were reduced gradually on 3 days and 7 days after treatment, but the APACHE II and SOFA scores on 7 days in group B were lower compared with group A (P < 0.05 and P < 0.01). CONCLUSION: HVHF and fluid resuscitation could reduce arterial lactate and cytokines contents, at the same time lower the APACHE II score and SOFA score in patients with refractory septic shock and MODS, thus it could improve the survival rate of MODS patients.

[Incidence and mortality risk factors of acute kidney injury in critical ill pregnancies: a single center retrospective analysis].

OBJECTIVE: To evaluate the incidence and mortality risk factors of pregnancy-related acute kidney injury (PR-AKI) in intensive care unit (ICU). METHODS: A retrospective analysis was conducted. Critically ill pregnancies admitted to ICU of Shandong University Affiliated Provincial Hospital from January 1st, 2012 to December 31st, 2016 were enrolled. Based on the Kidney Disease: Improving Global Outcomes (KDIGO)-acute kidney injury (AKI) criteria, patients were divided into two groups: PR-AKI group and non-PR-AKI group. Clinical characteristics and laboratory data of two groups were compared. Risk factors of incidence and mortality of PR-AKI patients were analyzed, and the receiver operating characteristic (ROC) curve was drawn to evaluate the value of these risk factors in predicting mortality of PR-AKI patients in ICU. RESULTS: (1) A total of 219 pregnancies in ICU were included in the analysis, 85 cases (38.8%) were diagnosed with PR-AKI, with 29.4% in AKI stage 1, 27.1% in AKI stage 2 and 43.5% in AKI stage 3. (2) Nineteen of 219 critically ill pregnancies died in ICU, the total ICU mortality was 8.7%. The mortality of PR-AKI group was higher than non-PR-AKI group (16.5% vs. 3.7%, P = 0.003). The mortality was worsened with increasing severity of AKI (4.0% for AKI stage 1, 4.3% for AKI stage 2, 32.4% for AKI stage 3). (3) Acute fatty liver of pregnancy (AFLP) and lactate (Lac) were the independent risk factors for PR-AKI [AFLP: odds ratio (OR) = 6.081, 95% confidence interval (95%CI) was 1.587-23.308, P = 0.008; Lac: OR = 1.460, 95%CI was 1.078-1.977, P = 0.014]. (4) Age, Lac, acute physiology and chronic health evaluation II (APACHE II) and sequential organ failure assessment (SOFA) were the independent risk factors associated with the mortality of PR-AKI patients in ICU (age: OR = 1.130, 95%CI was 1.022-1.249, P = 0.017; Lac: OR = 1.198, 95%CI was 1.009-2.421, P = 0.039; APACHE II: OR = 1.211, 95%CI was 1.102-1.330, P < 0.001; SOFA: OR = 1.411, 95%CI was 1.193-1.669, P < 0.001). (5) ROC curve analysis showed that age, Lac, APACHE II score and SOFA score all had good predictive values for in-hospital mortality among PR-AKI patients in ICU, the cut-off value was 29 years old, 3.8 mmol/L, 16 and 8, respectively, and the AUC was 0.751, 0.757, 0.892 and 0.919, respectively (all P < 0.01). CONCLUSIONS: The incidence and mortality of PR-AKI of critically ill pregnancies in ICU are high. Increased age, Lac, APACHE II score and SOFA score are independent risk factors associated with the mortality of PR-AKI patients in ICU, and have good predictive values for prognosis.

Growth inhibition and gene induction in human hepatocellular carcinoma cell exposed to sodium 4-phenylbutanoate.

BACKGROUND: Sodium 4-phenylbutanoate (NaPB) can induce cellular differentiation and cell cycle arrest. However, its potential anticancer properties in hepatocellular carcinoma and influence on normal liver cell are still unclear. We observed the effects of NaPB on growth inhibition, including differentiation and phase growth arrest in normal liver cell line L-02 and hepatocellular carcinoma cell line Bel-7402. Furthermore, we investigated its mechanism in Bel-7402. METHODS; Hepatocellular carcinoma cells Bel-7402 and normal liver cell line L-02 were treated with NaPB at different concentrations. Light microscopy was used to find morphological change in cells. Cell cycle was detected by flow cytometry. Expression of acetylating histone H4 and of histones deacetylase 4 (HDAC4) were determined by Western blot. The expression of P21WAF1/CIP1 and E-cadherin were observed through immunocytochemistry. RESULTS: NaPB treatment led to time dependent growth inhibition in hepatocellular carcinoma cells Bel-7402. NaPB treatment caused a significant decline in the fraction of S phase cells and a significant increase in G0/G1 cells. NaPB increased the expression of P21(WAF1/CIP1) and E-cadherin in Bel-7402 and significantly decreased the level of HDAC4 in Bel-7402. NaPB significantly improved the level of acetylating histone H4. The normal liver cell line L-02 showed no distinct changes under treatment with NaPB. CONCLUSIONS: NaPB inhibited the growth of hepatocellular carcinoma cells Bel-7402 and induced partial differentiation through enhancing the acetylating histones. In Bel-7402, the expressions of P21(WAF1/CIP1) and E-cadherin may be related to level of acetylating histones and inhibition of cellular growth. NaPB showed no significant effect on normal liver cells.

Genetic association of AKR1B1 gene polymorphism rs759853 with diabetic retinopathy risk: A meta-analysis.

OBJECTIVE: The study aimed to ascertain the correlation between AKR1B1 polymorphism rs759853 and the risk of diabetic retinopathy (DR) through a meta-analysis. METHODS: Crude odds ratios (ORs) and the corresponding 95% confidence interval (95% CIs) were calculated to assess the association of AKR1B1 rs759853 polymorphism with DR risk. Stratification analyses were further conducted based on ethnicity, diabetes mellitus (DM) type, Hardy-Weinberg equilibrium (HWE) status, and genotyping method. Heterogeneity was detected by Q test. Sensitivity analysis was implemented to check the robustness of final results. Additionally, Begg's funnel plot and Egger's test were used to evaluate underlying publication bias. RESULTS: Our meta-analysis ultimately incorporated 21 eligible publications with 22 independent case-control studies. The overall results demonstrated that AKR1B1 rs759853 polymorphism had no association with DR risk under all genetic models. However, after subgroup analysis by DM type, the rs759853 polymorphism was a protective factor against the DR onset in patients with type 1 DM (TT vs. CC: OR = 0.33, 95% CI = 0.17-0.67; TT + CT vs. CC: OR = 0.49, 95% CI = 0.36-0.68; TT vs. CC + CT: OR = 0.48, 95% CI = 0.28-0.83; allele T vs. allele C: OR = 0.56, 95% CI = 0.44-0.72; CT vs. CC: OR = 0.52, 95% CI = 0.37-0.74). Furthermore, subgroup analysis by genotyping method suggested that rs759853 genotyped using MassARRAY assay was significantly correlated with decreased risk of DR under dominate model (TT + CT vs. CC: OR = 0.71, 95%CI = 0.52-0.96). CONCLUSION: AKR1B1 polymorphism rs759853 may inhibit the occurrence of DR in patients with type 1 DM.

Effects of CCR5 59029G/A polymorphism on the risk to diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) causes high mortality in patients with diabetes mellitus and imposes heavy burden on individuals and society. In previous studies, various researches have investigated the association of DN with CCR5 59029G/A polymorphism, but relevant findings were controversial. Therefore, we performed this meta-analysis to obtain a conclusion on this issue. RESULTS: CCR5 59029G/A polymorphism showed significant risk-increasing effects on DN in all analyses under AA vs. GG, AA+GA vs. GG, AA vs. GG+GA, A vs. G and GA vs. GG model contrasts. Besides, a similar result was also obtained in Asian and type 2 diabetes mellitus groups under these five contrasts after subgroup analyses. METHODS: The relevant publications were searched from the electronic databases and other sources. The association intensity between CCR5 59029G/A polymorphism and DN susceptibility was measured using pooled odds ratios (ORs) with corresponding 95% confidence intervals (95% CIs). Inter-study heterogeneity was inspected with Q test, and sensitivity analysis was conducted to verify the stability of the final outcomes by removing one study each time in turn. Begg's funnel plot and Egger's test were utilized to examine publication bias among selected studies. CONCLUSION: CCR5 59029G/A polymorphism is significantly related to enhanced susceptibility to DN, especially in Asian populations and people with type 2 diabetes mellitus.

Effect of probiotics on the incidence of ventilator-associated pneumonia in critically ill patients: a randomized controlled multicenter trial.

PURPOSE: To evaluate the potential preventive effect of probiotics on ventilator-associated pneumonia (VAP). METHODS: This was an open-label, randomized, controlled multicenter trial involving 235 critically ill adult patients who were expected to receive mechanical ventilation for ≥48 h. The patients were randomized to receive (1) a probiotics capsule containing live Bacillus subtilis and Enterococcus faecalis (Medilac-S) 0.5 g three times daily through a nasogastric feeding tube plus standard preventive strategies or (2) standard preventive strategies alone, for a maximum of 14 days. The development of VAP was evaluated daily, and throat swabs and gastric aspirate were cultured at baseline and once or twice weekly thereafter. RESULTS: The incidence of microbiologically confirmed VAP in the probiotics group was significantly lower than that in the control patients (36.4 vs. 50.4 %, respectively; P = 0.031). The mean time to develop VAP was significantly longer in the probiotics group than in the control group (10.4 vs. 7.5 days, respectively; P = 0.022). The proportion of patients with acquisition of gastric colonization of potentially pathogenic microorganisms (PPMOs) was lower in the probiotics group (24 %) than the control group (44 %) (P = 0.004). However, the proportion of patients with eradication PPMO colonization on both sites of the oropharynx and stomach were not significantly different between the two groups. The administration of probiotics did not result in any improvement in the incidence of clinically suspected VAP, antimicrobial consumption, duration of mechanical ventilation, mortality and length of hospital stay. CONCLUSION: Therapy with the probiotic bacteria B. Subtilis and E. faecalis are an effective and safe means for preventing VAP and the acquisition of PPMO colonization in the stomach.

The role of O(6)-methylguanine-DNA methyltransferase polymorphisms in colorectal cancer susceptibility: a meta analysis.

OBJECTIVE: O(6)-methylguanine DNA methyl-transferase gene (MGMT) is a central DNA repair mechanism with a significant role in removing DNA damage caused by alkylating agents and inhibiting human oncogenesis. Two single polymorphisms in the MGMT gene, Leu84Phe and Ile143Val, have been reported to affect DNA repair capability and enzymic activity, thereby leading to formation of different cancers. In this work, we quantitatively assess the associations between MGMT polymorphisms and risk of colorectal cancer (CRC), as previous studies has implicated inconsistencies in their results. METHODS: Analysis was performed on all usable data collected from the eligible studies that were searched in multiple bibliographical databases (PubMed, SCOPUS, and Embase). RESULTS: We obtained studies on Leu84Phe and Ile143Val, providing 6,154 and 7,371 samples, respectively. In the analysis on Leu84Phe, the SNP presented no global association with CRC at both the genotypic and the allelic level, but a trend towards an increased or decreased risk was shown in the models examined. Stratification by ethnicity revealed a significant increase in risk of CRC related to the Phe/Phe genotype in Caucasian samples (homozygote genetic model: OR=1.70, 95% CI=1.06-2.72; recessive genetic model: OR=1.80, 95% CI=1.12-2.87). CONCLUSIONS: Based on the statistical data, our meta-analysis indicates that Leu84Phe polymorphism in the MGMT gene may predispose Caucasians to CRC.

[Study of the effects of high volume hemofiltration on extra vascular lung water and alveolar-arterial oxygen exchange in patients with septic shock].

OBJECTIVE: To explore the effects of high volume hemofiltration (HVHF) on inflammatory factors, extra vascular lung water and alveolar-arterial oxygen exchange in patients with septic shock. METHODS: The data of 87 patients with septic shock underwent fluid resuscitation admitted to intensive care unit (ICU) of Shandong Provincial Hospital Affiliated to Shandong University were retrospectively analyzed. According to whether HVHF was used or not, all the patients were divided into fluid resuscitation group (n=41) and HVHF group (n=46). The patients in HVHF group received bedside high volume continuous vein-vein hemofiltration for at least 3 days on the basis of fluid resuscitation. The inflammatory factors, indexes of heart function, hemodynamics monitored by pulse-indicated continuous cardiac output (PiCCO), oxygen exchange, the severity of the disease before and after treatment, and 28-day mortality were compared between the two groups. The relationship between extra-vascular lung water index (EVLWI) and alveolar-arterial oxygen pressure difference (P(A-a)DO2) was analyzed. RESULTS: (1) After treatment, the serum levels of interleukin-6 (IL-6), procalcitonin (PCT), and N-terminal pro-B-type natriuretic peptide (NT(-pro)BNP) in both group were gradually decreased. The IL-6, PCT, and NT(-pro)BNP on the 3rd day after treatment in HVHF group were significantly lower than those in fluid resuscitation group [IL-6 (µg/L): 34.8 ± 15.8 vs. 63.3 ± 21.2, PCT (µg/L): 7.5 ± 6.4 vs. 17.3 ± 11.2, NT(-pro)BNP (µg/L): 561.8 ± 23.7 vs. 584.3 ± 56.7, P<0.05 or P<0.01]. (2) The hemodynamics indexes were improved after treatment in both groups. The levels of intrathoracic blood volume index (ITBVI), EVLWI and pulmonary vascular permeability index (PVPI) on the 3rd day after treatment in HVHF group were significantly lower than those in fluid resuscitation group [ITBVI (mL/m²): 634.2 ± 125.8 vs. 963.8 ± 321.0, EVLWI (mL/kg): 7.5 ± 2.4 vs. 12.3 ± 4.2, PVPI: 2.2 ± 1.2 vs. 4.2 ± 2.0, all P<0.01]. (3) The levels of PA-aDO2and arterial blood lactic (Lac) were gradually decreased, and oxygenation index (PaO2/FiO2) was gradually increased in both groups. Compared with fluid resuscitation group, the P(A-a)DO2and Lac on the 3rd and the 7th day were significantly declined[P(A-a)DO2(mmHg, 1 mmHg=0.133 kPa) on the 3rd day: 252.37 ± 29.45 vs. 270.82 ± 38.07, on the 7th day: 181.08 ± 21.81 vs. 221.02 ± 29.13; Lac (mmol/L) on the 3rd day: 3.17 ± 2.03 vs. 4.07 ± 2.43, on the 7th day: 1.95 ± 0.97 vs. 2.45 ± 1.07, P<0.05 or P<0.01], and the PaO2/FiO2on the 7th day was significantly elevated (mmHg: 258 ± 41 vs. 178 ± 34, P<0.01). (4) A significant positive correlation was found between EVLWI and P(A-a)DO2(r=0.693, P=0.001), with the 95% confident interval (95% CI) 0.617-0.773. (5) The condition was improved after treatment in the two groups. The acute physiology and chronic health evaluationII (APACHEII) scores and sepsis-related organ failure assessment (SOFA) scores on the 7th day after treatment in HVHF group were significantly reduced compared with those in fluid resuscitation group (APACHEII score on the 3rd day: 18.2 ± 7.7 vs. 22.4 ± 8.6, on the 7th day: 8.2 ± 3.8 vs. 17.2 ± 6.8; SOFA score on the 3rd day: 13.6 ± 3.4 vs. 15.8 ± 5.0, on the 7th day: 7.6 ± 3.3 vs. 12.8 ± 3.9, P<0.05 or P<0.01). The 28-day mortality in HVHF group was significantly lower than that in fluid resuscitation group [15.22% (7/46) vs. 34.15% (14/41), χ² = 4.242, P=0.038]. CONCLUSIONS: HVHF could decrease blood inflammatory factors, and reduce the vaso-permeability and extra vascular lung water with a result of the improvement of the levels of alveolar- arterial oxygen exchange in patients with septic shock and the prognosis at the same time.