Reduced prosaposin levels in HepG2 cells with long-term coenzyme Q10 deficiency

Glycosphingolipids are involved in intercellular signaling, adhe­sion, proliferation, and differentiation. Saposins A, B, C, and D are cofactors required for glycosphingolipid hydrolysis. Saposins A–D are present in series in a common precursor protein, prosaposin. Thus, glycosphingolipids amounts depend on prosaposin cellular levels. We previously reported that prosaposin and saposin B bind coenzyme Q10 in human cells. Coenzyme Q10 is an essential lipid of the mitochondrial electron transport system, and its reduced form is an important antioxidant. Coenzyme Q10 level decrease in aging and in various progressive diseases. Therefore, it is interesting to understand the cellular response to long-term coenzyme Q10 deficiency. We established a long-term coenzyme Q10 deficient cell model by using the coenzyme Q10 biosynthesis inhibitor, 4-nitrobenzoate. The levels of coenzyme Q10 were reduced by 4-nitrobenzoate in HepG2 cells. Administration of 4-nitrobenzoate also decreased prosaposin protein and mRNA levels. The cellular levels of coenzyme Q10 and prosaposin were recovered by treatment with 4-hydroxybenzoquinone, a substrate for coenzyme Q10 synthesis that counteracts the effect of 4-nitrobenzoate. Furthermore, the ganglioside levels were altered in 4-nitrobenzoate treated cells. These results imply that long-term coenzyme Q10 deficiency reduces cellular prosaposin levels and disturbs glycosphingolipid metabolism.     

Interleukin-6 as a diagnostic marker for infection in critically ill patients: A systematic review and meta-analysis

Background

The ability of blood levels of interleukin (IL)-6 to differentiate between infection and non-infection in critically ill patients with suspected infection is unclear. We assessed the diagnostic accuracy of serum IL-6 levels for the diagnosis of infection in critically ill patients.

Being overweight or obese is associated with decreased mortality in critically ill patients: A retrospective analysis of a large regional Italian multicenter cohort

Purpose

To describe the epidemiology of obesity in a large cohort of intensive care unit (ICU) patients and study its impact on outcomes.

Methods

All 3902 patients admitted to one of 24 ICUs in the Piedmont region of Italy from April 3 to September 29, 2006, were included in this retrospective analysis of data from a prospective, multicenter study.

Results

Mean body mass index (BMI) was 26.0 ± 5.4 kg/m²: 32.8% of patients had a normal BMI, 2.6% were underweight, 45.1% overweight, 16.5% obese, and 2.9% morbidly obese. ICU mortality was significantly (P < .05) lower in overweight (18.8%) and obese (17.5%) patients than in those of normal BMI (22%). In multivariate logistic regression analysis, being overweight (OR = 0.73; 95%CI: 0.58-0.91, P = .007) or obese (OR = 0.62; 95%CI: 50.45-0.85, P = .003) was associated with a reduced risk of ICU death. Being morbidly obese was independently associated with an increased risk of death in elective surgery patients whereas being underweight was independently associated with an increased risk of death in patients admitted for short-term monitoring and after elective surgery.

Conclusions

In this cohort, overweight and obese patients had a reduced risk of ICU death. Being underweight or morbidly obese was associated with an increased risk of death in some subgroups of patients.     

Prosaposin regulates coenzyme Q10 levels in HepG2 cells,especially those in mitochondria

Coenzyme Q10 (CoQ10) is a key component of the mitochondrial electron transfer chain and is one of the most important cellular antioxidants. We previously reported that glycoprotein saposin B (SapB) binds CoQ10 in human cells. To elucidate the physiological role of SapB and its precursor, prosaposin (Psap), we prepared stable transfectants of HepG2 that overexpress wild-type human Psap (Wt-Tf). We also established a SapB domain mutated Psap (Mt-Tf) in which cysteine¹⁹⁸ was replaced with serine to disrupt three dimensional protein structure by the loss of S-S bridging. Psap knockdown (KD) strains were also examined. Western blotting analysis confirmed overexpression or knockdown of Psap in these HepG2 cells. The cellular ratios of CoQ10 to free cholesterol (FC) significantly decreased in the order of Wt-Tf>parental>Mt-Tf>KD. Additionally, the ratios of CoQ10/FC in mitochondrial fractions decreased in the order of Wt-Tf>parental>KD. These data indicate that Psap and/or SapB regulate CoQ10 levels in HepG2 cells, especially in their mitochondria.     

A novel COQ8A missense variant associated with a mild form of primary coenzyme Q10 deficiency type 4

BackgroundPrimary coenzyme Q10 deficiency refers to a group of diseases characterised by reduced levels of coenzyme Q10 in related tissues or cultured cells associated with the 9 genes involved in the biosynthesis of coenzyme Q10. A biallelic pathogenic variant of COQ8A gene causes the occurrence of the primary coenzyme Q10 deficiency type 4. The objective of this study was to investigate the genetic cause of muscle weakness in a proband who had a negative DMD gene test for Becker muscular dystrophy.MethodsThe DNA of the proband was sequenced using whole exome sequencing. With the help of the Human Phenotype Ontology (HPO), the range of related candidate pathogenic genes has been reduced to a certain extent based on “muscle weakness” (HP:0001324). In addition, family linkage analysis, phenotypic-genotype check and protein structure modeling were used to explore the genetic cause of the proband.ResultsThe compound heterozygous variant c.836A > C (p.Gln279Pro) and c.1228C > T (p.Arg410Ter) in the COQ8A gene was identified in the proband. According to the 2015 American College of Medical Genetics and Genomics (ACMG) standards and guidelines for the interpretation of sequence variants, the novel variant c.836A > C could be classified as “likely pathogenic” for the proband.ConclusionThe p.Gln279Pro was detected in the KxGQ motif and the QKE triplet of the COQ8A protein, whose structures were crucial for the structure and function of the COQ8A protein associated with the biosynthesis of coenzyme Q10 and the proband's clinical symptoms were relatively milder than those previously reported.     

大剂量辅酶Q10静脉滴注治疗难治性心力衰竭的疗效观察

对３３例心功能Ⅲ～Ⅳ级的难治性心力衰竭患者，应用大剂量辅酶Ｑ１０静滴治疗后心功能显著改善，总有效率８４．８％。并与３０例应用洋地黄、利尿、扩血管剂治疗的患者对比，发现前者疗效显著，氧分压明显提高（Ｐ＜０．０１），心搏量及射血分数显著改善（Ｐ＜０．０１）。停用辅酶Ｑ１０治疗后，大部分患者（８３．０％）症状复发，再次治疗仍有效，未见严重副反应。提示辅酶Ｑ１０是治疗难治性心力衰竭的有效药物，大剂量静滴，疗效迅速     

阿托伐他汀联合辅酶Q10对心肌梗死后心力衰竭大鼠解偶联蛋白2基因表达的影响

目的研究阿托伐他汀及辅酶Q10通过抗氧化作用改善心衰大鼠的作用机制。方法结扎大鼠左冠状动脉前降支并饲养6周的24只存活大鼠随机分为假手术组（Shamgroup,n=6）、模型组（Model group,n=6）、阿托伐他汀组（atorvastatin group,n=6）、阿托伐他汀＋辅酶Q10组（atorvastatin＋coenzyme Q10 group,n=6）,连续灌胃给药5周后测定大鼠血流动力学参数,全心及左室肥厚指数（HW/BW,LVHW/BW）,血清SOD活性及MDA含量,RT-PCR法测定非梗死区心肌组织UCP2 mRNA表达水平。结果联合应用阿托伐他汀及辅酶Q10更能明显升高左心室内压最大上升、最大下降速率（±dp/dtmax）及SOD活性,降低左心室收缩压（LVSP）、左心室舒张末压（LVEDP）、心肌肥厚指数、血清MDA的含量及下调UCP2 mRNA表达水平（P〈0.05-0.001）,但对心率（HR）、收缩压（SBP）、舒张压（DBP）无明显影响（P〉0.05）。结论阿托伐他汀联合辅酶Q10可能通过抗氧化作用,下调心肌梗死后心衰大鼠心肌细胞内UCP2 mRNA的表达水平改善心衰心室重构过程中能量代谢。     

High circulating N-terminal pro-B-type natriuretic peptide is associated with greater systolic cardiac dysfunction and nonresponsiveness to fluids in septic vs nonseptic critically ill patients

Purpose

It is still unclear whether circulating levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP) reflect cardiac filling and function in the critically ill patient, particularly during sepsis and a proinflammatory response that may induce NT-proBNP release from the heart.

Materials and Methods

We prospectively evaluated the value of NT-proBNP as a marker of cardiac loading, function, and response to fluid loading in 18 septic and 68 nonseptic, critically ill patients in the intensive care unit of a university medical center. Transpulmonary thermal dilution and pressure measurements were done, and plasma NT-proBNP was determined before and after colloid fluid loading.

Results

Compared with nonseptic patients, NT-proBNP plasma levels were higher and systolic cardiac function indices were lower in patients with sepsis than those without sepsis. N-terminal pro-B-type natriuretic peptide best related, from all hemodynamic parameters before and after fluid loading, to systolic cardiac function (rather than diastolic filling) variables, independently of confounders such as renal dysfunction (judged from serum creatinine). In addition, a high NT-proBNP (>3467 pg/mL) predicted absence of fluid responsiveness in sepsis only.

Conclusions

Our data suggest that an increased circulating NT-proBNP plasma level is an independent marker of greater systolic cardiac dysfunction, irrespective of filling status, and is a better predictor of fluid nonresponsiveness in septic vs nonseptic, critically ill patients.     

甲状腺激素对危重症患者病情严重程度的评估

目的 探讨甲状腺激素在危重患者的变化及与其严重程度的关系.方法 选择2009年1-12月我院加强监护病房住院的92例合并非甲状腺疾病综合征(NTIS)危重症患者,记录一般情况,计算急性生理和慢性健康状况评分(APACHEⅡ)评分,检测入科次日甲状腺激素.分析甲状腺激素水平和患者病情严重程度之间是否有相关性.结果 脓毒症休克组患者甲状腺激素,三碘甲状腺原氨酸(TT3)(1.16±0.24)nmol/L、甲状腺素总量(TT4)(68.93±24.11)nmol/L、游离三碘甲状腺原氨酸(FT3)(3.76±0.21)pmol/L,游离甲状腺素(FT4)(16.40±2.74)pmol/L,促甲状腺激素(TSH)(1.58±1.01)mU/L低于非脓毒症休克组TT3(1.50±0.25)nmol/L、TT4(91.70±21.90)nmol/L、FT3(4.24±0.45)pmol/L、FT4(17.98±3.28)pmol/L、TSH(2.43±2.76)mU/L,差异均有统计学意义(P均＜0.05).脓毒症休克组FT3、FT4水平与APACHEⅡ评分具有相关性(r值分别为-0.694、-0.613,P均＜0.05).结论 重症患者甲状腺激素水平低,与病情严重程度具有相关性.     

Glucocorticoid receptor mRNA levels are selectively decreased in neutrophils of children with sepsis

Objective  Corticosteroids are used in sepsis treatment to benefit outcome. However, discussion remains on which patients will benefit from treatment. Inter-individual variations in cortisol sensitivity, mediated through the glucocorticoid receptor, might play a role in the observed differences. Our aim was to study changes in mRNA levels of three glucocorticoid receptor splice variants in neutrophils of children with sepsis. Patients and design  Twenty-three children admitted to the pediatric intensive care unit with sepsis or septic shock were included. Neutrophils were isolated at days 0, 3 and 7, and after recovery (>3 months). mRNA levels of the glucocorticoid receptor splice variants GR-α (determining most of the cortisol effect), GR-P (increasing GR-α effect) and GR-β (inhibitor of GR-α) were measured quantitatively. Main results  Neutrophils from sepsis patients showed decreased levels of glucocorticoid receptor mRNA of the GR-α and GR-P splice variants on day 0 compared to after recovery. GR-α and GR-P mRNA levels showed a gradual recovery on days 3 and 7 and normalized after recovery. GR-β mRNA levels did not change significantly during sepsis. GR expression was negatively correlated to interleukin-6 (a measure of disease severity, r = −0.60, P = 0.009). Conclusions  Children with sepsis or septic shock showed a transient depression of glucocorticoid receptor mRNA in their neutrophils. This feature may represent a tissue-specific adaptation during sepsis leading to increased cortisol resistance of neutrophils. Our study adds to understanding the mechanism of cortisol sensitivity in immune cells. Future treatment strategies, aiming at timing and tissue specific regulation of glucocorticoids, might benefit patients with sepsis or septic shock.     

Effect of coenzyme Q10 supplementation on fatigue: A systematic review of interventional studies

AimsA number of studies have examined the beneficial effects of Coenzyme Q10 (CoQ10) on fatigue in different population, but the findings have been inconclusive. Herein, we systematically reviewed available interventional studies to elucidate the overall effects of CoQ10 supplementation on fatigue among adolescent and adult population.MethodsPubMed, Cochrane's library, Science direct, Scopus, Google scholar and ISI web of science databases were searched for all available literature until April 2018 for studies assessing the effects of CoQ10 supplementation on fatigue. The Cochrane bias assessment tool were used to assess the quality of studies.ResultsA total of 16 studies out of 1316 met our inclusion criteria and included in our systematic review. Among included studies 10 of them showed significant beneficial effects (p < 0.05) of CoQ10 supplementation on fatigue status among healthy, fibromyalgia, statin-related fatigue, multiple sclerosis and end-stage heart failure subjects. CoQ10 supplementation could alleviate fatigue, but differences between studies population should be taken into account.ConclusionIt seems CoQ10 has better therapeutic effects in statin-related fatigue and fibromyalgia patients compared with the other disease related fatigue. Finally, in order to draw a firm link between CoQ10 and fatigue, more clinical trials with adequate sample size and with sufficient follow-up periods are needed.     

Improved survival of critically ill cancer patients with septic shock

Objective To identify predictors of 30-day mortality in critically ill cancer patients with septic shock.Design Retrospective study over a 6-year period.Setting Twelve-bed medical intensive care unit (ICU).Patients Eighty-eight patients (55 men, 33 women) aged 55 (43.5–63) years admitted to the ICU for septic shock.Interventions None.Measurements and main results Eighty (90.9%) patients had hematological malignancies and eight (9.1%) had solid tumors; 47 patients (53.4%) were neutropenic, 19 (21.6%) were hematopoietic stem cell transplantation (HSCT) recipients, and 27 (30.7%) were in remission. Microbiologically documented infections were found in 60 (68.2%) patients. The Simplified Acute Physiologic Score II (SAPS II) and Logistic Organ Dysfunction (LOD) scores at ICU admission were 66 (47–89) and 7 (5–10), respectively, and the LOD score on day 3 was 8 (4–10). Sixty-eight (78.1%) patients received invasive mechanical ventilation (MV), 12 (13.6%) noninvasive MV, 22 (25%) dialysis. Thirty-day mortality was 65.5% (57/88). By multivariable analysis, mortality was higher when time to antibiotic treatment was >2 h [odds ratio (OR), 7.05; 95% confidence interval (95% CI), 1.17–42.21] and when DLOD (day 3–day 1 LOD score/day 3 LOD score) was high (OR, 3.47; 95% CI, 1.44–8.39); mortality was lower when admission occurred between 1998 and 2000 (OR, 0.23; 95% CI, 0.05–0.98) and when initial antibiotics were adapted (OR, 0.24; 95% CI, 0.06–0.09).Conclusions Earlier ICU admission and antibiotic treatment of critically ill cancer patients with septic shock is associated with higher 30-day survival. The LOD score change on day 3 as compared to admission is useful for predicting survival.Funding: none     

Stabilizing life: A grounded theory of surviving critical illness

ObjectivesThe experience of critical illness among patients is both complex and multifaceted. It can make patients vulnerable to long-term consequences such as impairment in cognition, mental health and physical functional ability which affects health related quality of life. This study aims to explore patients’ patterns of behaviour during the process from becoming critical ill to recovery at home.DesignWe used a classic grounded theory methodology to explore the main concern for intensive care patients. Thirteen participants were interviewed and seven different participants were observed.SettingThree general intensive care units in Sweden, consisting of a university hospital, a county hospital and a district hospital.FindingsThe theory Stabilizing life explains how patients’ main concern, being out of control, can be resolved. This theory involves two processes, recapturing life and recoding life, and one underlying strategy, emotional balancing that is used during the whole process.ConclusionThe process from becoming critically ill until recovery home is perceived as a constant fight in actions and mind to achieve control and stabilize life. This theory can form the basis for further qualitative and quantitative research about interventions that promotes wellbeing during the whole process.     

Effects of simvastatin on blood lipids, vitamin E, coenzyme Q10 levels and left ventricular function in humans

BACKGROUND: As statin therapy has been reported to reduce antioxidants such as vitamin E and coenzyme Q10 and there are indications that this reduction may cause impairment of left ventricular function (LVF), we studied the influence of simvastatin on LVF and serum vitamin E and coenzyme Q10 levels in humans. MATERIAL AND METHODS: We assessed the effect of simvastatin on left ventricular function and coenzyme Q10 levels in 21 (11 male, 10 female) hypercholesterolaemic subjects (mean age = 56 years) with normal LVF, over a period of 6 months. Subjects were re-tested after a 1-month wash-out period (7 months). Echocardiography was performed on all subjects before commencement of simvastatin (20 mg day(-1)), and at 1, 3, 6 and 7 months after initiation of treatment. Fasting blood samples were also collected at these intervals to assess lipids, apoproteins, vitamin E and coenzyme Q10. RESULTS: Serum lipids showed the expected reductions. Plasma vitamin E and coenzyme Q10 levels were reduced by 17 +/- 4% (P < 0.01) and 12 +/- 4% (P < 0.03) at 6 months. However, the coenzyme Q10/LDL-cholesterol ratio and vitamin E/LDL-cholesterol ratio increased significantly. Left ventricular ejection fraction (EF) decreased transiently after 1 month, while no significant change was observed at 3 and 6 months. Other markers of left ventricular function did not change significantly at any time point. CONCLUSION: Despite reduced plasma vitamin E and coenzyme Q10, 20 mg of simvastatin therapy is associated with a significantly increased coenzyme Q10/LDL-cholesterol ratio and vitamin E/LDL-cholesterol ratio. Simvastatin treatment is not associated with impairment in left ventricular systolic or diastolic function in hypercholesterolaemic subjects after 6 months of treatment.     

Acute kidney injury in septic shock: clinical outcomes and impact of duration of hypotension prior to initiation of antimicrobial therapy

Objective  To describe the incidence and outcomes associated with early acute kidney injury (AKI) in septic shock and explore the association between duration from hypotension onset to effective antimicrobial therapy and AKI. Design  Retrospective cohort study. Subjects  A total of 4,532 adult patients with septic shock from 1989 to 2005. Setting  Intensive care units of 22 academic and community hospitals in Canada, the United States and Saudi Arabia. Measurements and main results  In total, 64.4% of patients with septic shock developed early AKI (i.e., within 24 h after onset of hypotension). By RIFLE criteria, 16.3% had risk, 29.4% had injury and 18.7% had failure. AKI patients were older, more likely female, with more co-morbid disease and greater severity of illness. Of 3,373 patients (74.4%) with hypotension prior to receiving effective antimicrobial therapy, the median (IQR) time from hypotension onset to antimicrobial therapy was 5.5 h (2.0–13.3). Patients with AKI were more likely to have longer delays to receiving antimicrobial therapy compared to those with no AKI [6.0 (2.3–15.3) h for AKI vs. 4.3 (1.5–10.8) h for no AKI, P < 0.0001). A longer duration to antimicrobial therapy was also associated an increase in odds of AKI [odds ratio (OR) 1.14, 95% CI 1.10–1.20, P < 0.001, per hour (log-transformed) delay]. AKI was associated with significantly higher odds of death in both ICU (OR 1.73, 95% CI 1.60–1.9, P < 0.0001) and hospital (OR 1.62, 95% CI, 1.5–1.7, P < 0.0001). By Cox proportional hazards analysis, including propensity score-adjustment, each RIFLE category was independently associated with a greater hazard ratio for death (risk 1.31; injury 1.45; failure 1.56). Conclusion  Early AKI is common in septic shock. Delays to appropriate antimicrobial therapy may contribute to significant increases in the incidence of AKI. Survival was considerably lower for septic shock associated with early AKI, with increasing severity of AKI, and with increasing delays to appropriate antimicrobial therapy.     

Molecular mechanisms underlying the promotion of wound repair by coenzyme Q10: PI3K/Akt signal activation via alterations to cell membrane domains

Coenzyme Q10 (CoQ10) promotes wound healing in vitro and in vivo. However, the molecular mechanisms underlying the promoting effects of CoQ10 on wound repair remain unknown. In the present study, we investigated the molecular mechanisms through which CoQ10 induces wound repair using a cellular wound-healing model. CoQ10 promoted wound closure in a dose-dependent manner and wound-mediated cell polarization after wounding in HaCaT cells. A comparison with other CoQ homologs, benzoquinone derivatives, and polyisoprenyl compounds suggested that the whole structure of CoQ10 is required for potent wound repair. The phosphorylation of Akt after wounding and the plasma membrane translocation of Akt were elevated in CoQ10-treated cells. The promoting effect of CoQ10 on wound repair was abrogated by co-treatment with a phosphatidylinositol 3-kinase (PI3K) inhibitor. Immuno­histochemical and biochemical analyses showed that CoQ10 increased the localization of caveolin-1 (Cav-1) to the apical membrane domains of the cells and the Cav-1 content in the membrane-rich fractions. Depletion of Cav-1 suppressed CoQ10-mediated wound repair and PI3K/Akt signaling activation in HaCaT cells. These results indicated that CoQ10 increases the translocation of Cav-1 to the plasma membranes, activating the downstream PI3K/Akt signaling pathway, and resulting in wound closure in HaCaT cells.     

A five-year study of severe community-acquired pneumonia with emphasis on prognosis in patients admitted to an intensive care unit

Objectives To characterize the epidemiology and to determine the prognosis factors in severe community-acquired pneumonia among patients admitted to an intensive care unit. Design Retrospective clinical study. Setting Intensive Care and Infectious Diseases Unit of a municipal general hospital of Lille University Medical School. Patients 299 consecutive patients exhibiting severe community-acquired pneumonia. Measurements and results On admission to ICU, 149 patients required mechanical ventilation for acute respiratory failure and 44 exhibited septic shock. Pulmonary involvement was bilateral in 71 patients. There were 260 organisms isolated from 197 patients (65.9%), the most frequent beingStreptococcus pneumoniae (n=80),Staphylococcus spp. (n=57) and Gram-negative bacilli (n=81). Overall mortality was 28.5% (85 patients). According to univariate analysis, mortality was associated with age over 60 years, anticipated death within 5 years, immunosuppression, shock, mechanical ventilation, bilateral pulmonary involvement, bacteremia, neutrophil count <3500/mm³, total serum protein level <45 g/l, serum creatinine >15 mg/l, non-aspiration pneumonia, ineffective initial therapy and complications. Multivariate analysis selected only 5 factors significantly associated with prognosis: anticipated death within 5 years, shock, bacteremia, non-pneumonia-related complications and ineffective initial therapy. Conclusion The effectiveness of the initial therapy appears to be the most significant prognosis factor and, as the one and only related to the initial medical intervention, suggests a need for permanent optimization of our antimicrobial strategies. Study presented at the 6th European Congress on Intensive Care Medicine, 1992, Barcelona, Spain     

Ionized calcium level predicts in-hospital mortality of severe sepsis patients: A retrospective cross-sectional study

Objective: To evaluate the effect of serum ionized calcium levels on the prognosis of severe sepsis patients. Methods: This retrospective cross-sectional study included sepsis patients who were hospitalized in an intensive care unit between January 2011 and December 2014. The demographic and baseline data of the patients who died and survived were compared. The cutoff value of ionized calcium for in-hospital mortality was determined by the receiver operating characteristics curve (ROC). In-hospital mortalities and the survival rates were compared between patients with different ionized calcium levels. Besides, the risk factor of in-hospital mortality was determined. Results: This study included 145 patients with 113 patients who died in the hospital. The patients who died had significantly lower ionized calcium levels (U=2.25, P=0.034). A cut-off value of 0.93 mmol/L of ionized calcium was determined by the ROC curve. The patients with ionized calcium>0.93 mmol/L showed a significantly lower morality (χ2=9.90, P=0.002) and higher survival rate than with ≤0.93 mmol/L (log rank=6.20, P=0.010). Multivariate Cox regression revealed that ionized calcium ≤0.93 mmol/L was a risk factor of in-hospital mortality. Conclusions: Ionized calcium level≤0.93 mmol/L was an independent predictor of in-hospital mortality of severe sepsis.