Circulating MicroRNA-150 Serum Levels Predict Survival in Patients with Critical Illness and Sepsis

Background and Aims

Down-regulation of miR-150 was recently linked to inflammation and bacterial infection. Furthermore, reduced serum levels of miR-150 were reported from a small cohort of patients with sepsis. We thus aimed at evaluating the diagnostic and prognostic value of miR-150 serum levels in patients with critically illness and sepsis.

Methods

miR-150 serum levels were analyzed in a cohort of 223 critically ill patients of which 138 fulfilled sepsis criteria and compared to 76 healthy controls. Results were correlated with clinical data and extensive sets of routine and experimental biomarkers.

Results

Measurements of miR-150 serum concentrations revealed only slightly reduced miR-150 serum levels in critically ill patients compared to healthy controls. Furthermore miR-150 levels did not significantly differ in critically ill patients with our without sepsis, indicating that miR-150 serum levels are not suitable for diagnostic establishment of sepsis. However, serum levels of miR-150 correlated with hepatic or renal dysfunction. Low miR-150 serum levels were associated with an unfavorable prognosis of patients, since low miR-150 serum levels predicted mortality with high diagnostic accuracy compared with established clinical scores and biomarkers.

Conclusion

Reduced miR-150 serum concentrations are associated with an unfavorable outcome in patients with critical illness, independent of the presence of sepsis. Besides a possible pathogenic role of miR-150 in critical illness, our study indicates a potential use of circulating miRNAs as a prognostic rather than diagnostic marker in critically ill patients.     

Studies on the Longevity,Sequestration and Release of the Leukocytes in Chronic Myelogenous Leukemia

The intravascular life-span of leukocytes labelled in vitro with radioactive di-isopropylfluorophosphate was studied in 12 patients with chronic myelogenous leukemia (CML). In relapse, leukocyte specific activity (LSA) disappeared slowly; in remission, LSA curves approached normal and only a small proportion of LSA disappeared slowly. The level of maturation of the leukocytes that persisted in the blood was investigated by a leukocyte fractionation technique which excluded immature myeloid cells from leukocyte samples. The influence of extracorpuscular factors upon the pattern of disappearance of LSA was investigated by means of cross-transfusion experiments, and LSA curves obtained with in vitro and in vivo labelling were compared. The results suggest that: (1) the intravascular life-span of the mature leukemic neutrophil is prolonged in relapse and in remission; (2) intrinsically abnormal leukocytes are sequestered in an extravascular pool(s) but recycling occurs; (3) extracorpuscular factors modify the LSA curves; (4) exchange of leukocytes between intravascular and extravascular pools may not occur in relapse; and (5) the intravascular and extravascular pools constitute a self-sustaining pool(s) not replenished from a non-miscible precursor pool.     

Altered Mitochondrial Function and Oxidative Stress in Leukocytes of Anorexia Nervosa Patients

Context

Anorexia nervosa is a common illness among adolescents and is characterised by oxidative stress.

Objective

The effects of anorexia on mitochondrial function and redox state in leukocytes from anorexic subjects were evaluated.

Design and setting

A multi-centre, cross-sectional case-control study was performed.

Patients

Our study population consisted of 20 anorexic patients and 20 age-matched controls, all of which were Caucasian women.

Main outcome measures

Anthropometric and metabolic parameters were evaluated in the study population. To assess whether anorexia nervosa affects mitochondrial function and redox state in leukocytes of anorexic patients, we measured mitochondrial oxygen consumption, membrane potential, reactive oxygen species production, glutathione levels, mitochondrial mass, and complex I and III activity in polymorphonuclear cells.

Results

Mitochondrial function was impaired in the leukocytes of the anorexic patients. This was evident in a decrease in mitochondrial O₂ consumption (P<0.05), mitochondrial membrane potential (P<0.01) and GSH levels (P<0.05), and an increase in ROS production (P<0.05) with respect to control subjects. Furthermore, a reduction of mitochondrial mass was detected in leukocytes of the anorexic patients (P<0.05), while the activity of mitochondrial complex I (P<0.001), but not that of complex III, was found to be inhibited in the same population.

Conclusions

Oxidative stress is produced in the leukocytes of anorexic patients and is closely related to mitochondrial dysfunction. Our results lead us to propose that the oxidative stress that occurs in anorexia takes place at mitochondrial complex I. Future research concerning mitochondrial dysfunction and oxidative stress should aim to determine the physiological mechanism involved in this effect and the physiological impact of anorexia.     

水位对黑斑侧褶蛙蝌蚪形态表型、白细胞数量和应激反应的影响

为探究水位变化对黑斑侧褶蛙（Pelophylaxnigromaculatus）蝌蚪形态表型、免疫功能和应激反应能力的影响,实验室内测定了水位恒定组以及水位快速、中速和慢速下降组37期蝌蚪发育至变态完成期的变态时长、身体大小和血液中各型白细胞的百分比,以及嗜中性粒细胞与淋巴细胞比值的变化。结果表明,水位快速下降显著缩短了蝌蚪的变态时长（P <0.05）,体长下降明显（P <0.05）,体重和体宽有所降低,但组间差异不显著（P> 0.05）。嗜中性粒细胞的百分比快速下降组显著高于其他处理组,单核细胞的百分比水位恒定组显著高于中速下降组（P <0.05）,嗜酸性粒细胞、嗜碱性粒细胞和淋巴细胞的百分比均无明显的组间差异（P>0.05）;嗜中性粒细胞与淋巴细胞比值快速下降组显著高于其他处理组（P <0.05）。水位加速下降导致登陆后幼蛙的个体变小,由嗜中性粒细胞和单核细胞所代表的天然免疫能力变化趋势不同,应激反应能力增强,可能不利于幼蛙的存活。     

Mutations in the Mitochondrial Atp Synthase Gamma Subunit Suppress a Slow-Growth Phenotype of Yme1 Yeast Lacking Mitochondrial DNA

In Saccharomyces cerevisiae, inactivation of the nuclear gene YME1 causes several phenotypes associated with impairment of mitochondrial function. In addition to deficiencies in mitochondrial compartment integrity and respiratory growth, yme1 mutants grow extremely slowly in the absence of mitochondrial DNA. We have identified two genetic loci that, when mutated, act as dominant suppressors of the slow-growth phenotype of yme1 strains lacking mitochondrial DNA. These mutations only suppressed the slow-growth phenotype of yme1 strains lacking mitochondrial DNA and had no effect on other phenotypes associated with yme1 mutations. One allele of one linkage group had a collateral respiratory deficient phenotype that allowed the isolation of the wild-type gene. This suppressing mutation was in ATP3, a gene that encodes the gamma subunit of the mitochondrial ATP synthase. Recovery of two of the suppressing ATP3 alleles and subsequent sequence analysis placed the suppressing mutations at strictly conserved residues near the C terminus of Atp3p. Deletion of the ATP3 genomic locus resulted in an inability to utilize nonfermentable carbon sources. atp3 deletion strains lacking mitochondrial DNA grew slowly on glucose media but were not as compromised for growth as yme1 yeast lacking mitochondrial DNA.     

L-Carnitine Prevents Progression of Non-Alcoholic Steatohepatitis in a Mouse Model with Upregulation of Mitochondrial Pathway

Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease characterized by lobular inflammation, hepatocellular ballooning, and fibrosis with an inherent risk for progression to cirrhosis and hepatocellular carcinoma (HCC). Mitochondrial dysfunction appears to play a role in the progression from simple steatosis to NASH. L-carnitine (L-b-hydroxy-g-N-trimethylaminobutyric acid), an essential nutrient that converts fat into energy in mitochondria, has been shown to ameliorate liver damage. The aim of the present study was to explore the preventive and therapeutic effect of L-carnitine in NASH model mice. Eight-week-old male STAM mice, a NASH-cirrhosis-hepatocarcinogenic model, were divided into 3 experimental groups and fed as follows: 1) high-fat diet (HFD) (control group); 2) HFD mixed with 0.28% L-carnitine (L-carnitine group); and 3) HFD mixed with 0.01% α-tocopherol (α-tocopherol group). After 4 or 8 weeks, mice were sacrificed. Blood samples and livers were collected, and hepatic tumors were counted and measured. Livers were subjected to histological study, immunohistochemical staining of 4-hydroxynonenal and ferritin, determination of 8-OHdG levels, mRNA and protein expressions for multiple genes, and metabolomic analysis. The intestinal microbiome was also analyzed. L-carnitine increased hepatic expression of genes related to long-chain fatty acid transport, mitochondrial β-oxidation, and antioxidant enzymes following suppression of hepatic oxidative stress markers and inflammatory cytokines in NASH, and mice treated with L-carnitine developed fewer liver tumors. Although α-tocopherol resulted in NASH improvement in the same manner as L-carnitine, it increased periodontitis-related microbiotic changes and hepatic iron transport-related gene expression and led to less effective for anti-hepatocarcinogenesis.

Conclusion

L-carnitine prevents progression of non-alcoholic steatohepatitis in a mouse model by upregulating the mitochondrial β-oxidation and redox system.     

Detailed Characterization of Brain Dysfunction in a Long-Term Rodent Model of Critical Illness

Neurochemical Research - Critical illness encompasses a wide spectrum of life-threatening clinical conditions requiring intensive care. Our objective was to evaluate cognitive, inflammatory and...     

Cytoprotective and immunomodulatory properties of Geriforte, a herbomineral preparation, in lymphocytes

The study was designed to determine the cytoprotective and immunomodulatory properties of Geriforte, an indigenous herbomineral compound, using lymphocytes as a model system. The possible involvement of free radicals and the ability of Geriforte to inhibit the oxidative process induced by tert-butylhydroperoxide (tert-BHP) was also investigated. The production of free radicals (evaluated by fluorescent probe fluorescein-diacetate), level of malondialdehyde (MDA, as index of lipid peroxidation), and levels of anti-oxidants – reduced glutathione (GSH) and glutathione peroxidase (GPx) were determined. There was an increase in cytotoxicity and apoptosis significantly in the presence of tert-BHP (100 μM) over control. Addition of tert-BHP resulted in a marked increase in free radical production and MDA level with a concomitant decrease in GSH level in lymphocytes. Geriforte supplementation reduced cytotoxicity and apoptosis induced by tert-BHP. Further, Geriforte inhibited tert-BHP induced lipid peroxidation and maintained higher anti-oxidant levels. tert-BHP significantly inhibited the lymphocyte proliferation stimulated by mitogens (Lipopolysaccharide/Concanavalin A) and enhanced DNA fragmentation. Geriforte relieved the inhibitory effect of tert-BHP on lymphocyte proliferation and decreased DNA fragmentation appreciably. The results indicate that Geriforte possesses cytoprotective and immunomodulatory properties which could be due to its anti-oxidant activity.     

Each Monomer of the Dimeric Accessory Protein for Human Mitochondrial DNA Polymerase Has a Distinct Role in Conferring Processivity

The accessory protein polymerase (pol) γB of the human mitochondrial DNA polymerase stimulates the synthetic activity of the catalytic subunit. pol γB functions by both accelerating the polymerization rate and enhancing polymerase-DNA interaction, thereby distinguishing itself from the accessory subunits of other DNA polymerases. The molecular basis for the unique functions of human pol γB lies in its dimeric structure, where the pol γB monomer proximal to pol γA in the holoenzyme strengthens the interaction with DNA, and the distal pol γB monomer accelerates the reaction rate. We further show that human pol γB exhibits a catalytic subunit- and substrate DNA-dependent dimerization. By duplicating the monomeric pol γB of lower eukaryotes, the dimeric mammalian proteins confer additional processivity to the holoenzyme polymerase.     

Hemoglobin mass in humans during a space flight and its simulation

The review is a retrospective of the studies on body fluids and the hematopoietic system during long space missions and physiological simulation, in particular, the noninvasive carbon monoxide method of the determination of hemoglobin mass. The method is used to assess protein synthesis in general and the mass of the circulating blood. In microgravity, the amount of extracellular fluid, including blood plasma, hydration level, hemoglobin, and hematocrit, decrease. The number of erythrocytes also decreases, which is followed by the appearance of their abnormal forms. All these alterations are responsible for the so-called erythrocytopenic syndrome observed in microgravity. The possible factors and mechanisms of syndrome development and its dependence on the level of body hydration are discussed. The review attempts to generalize and interpret the known results and the up-to-date state of these investigations.     

Circulating Levels of Fatty Acid-Binding Protein Family and Metabolic Phenotype in the General Population

Objective

Fatty acid-binding proteins (FABPs) are a family of 14-15-kDa proteins, and some FABPs have been to be used as biomarkers of tissue injury by leak from cells. However, recent studies have shown that FABPs can be secreted from cells into circulation. Here we examined determinants and roles of circulating FABPs in a general population.

Methods

From the database of the Tanno-Sobetsu Study, a study with a population-based cohort design, data in 2011 for 296 subjects on no medication were retrieved, and FABP1∼5 in their serum samples were assayed.

Results

Level of FABP4, but not the other isoforms, showed a gender difference, being higher in females than in males. Levels of all FABPs were negatively correlated with estimated glomerular filtration rate (eGFR), but a distinct pattern of correlation with other clinical parameters was observed for each FABP isoform; significant correlates were alanine aminotransferase (ALT), blood pressure (BP), and brain natriuretic peptide (BNP) for FABP1, none besides eGFR for FABP2, age, BP, and BNP for FABP3, age, waist circumference (WC), BP, BNP, lipid variables, high-sensitivity C-reactive protein (hsCRP), and HOMA-R for FABP4, and age, WC, BP, ALT, BNP, and HOMA-R for FABP5. FABP4 is the most strongly related to metabolic markers among FABPs. In a multivariate regression analysis, FABP4 level was an independent predictor of HOMA-R after adjustment of age, gender, WC, BP, HDL cholesterol, and hsCRP.

Conclusions

Each FABP isoform level showed a distinct pattern of correlation with clinical parameters, although levels of all FABPs were negatively determined by renal function. Circulating FABP4 appears to be a useful biomarker for detecting pre-clinical stage of metabolic syndrome, especially insulin resistance, in the general population.     

Redondoviridae,a Family of Small,Circular DNA Viruses of the Human Oro-Respiratory Tract Associated with Periodontitis and Critical Illness

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Downregulation of Mitochondrial Porin Inhibits Cell Growth and Alters Respiratory Phenotype in Trypanosoma brucei

Porin is the most abundant outer membrane (OM) protein of mitochondria. It forms the aqueous channel on the mitochondrial OM and mediates major metabolite flux between mitochondria and cytosol. Mitochondrial porin in Trypanosoma brucei, a unicellular parasitic protozoan and the causative agent of African trypanosomiasis, possesses a β-barrel structure similar to the bacterial OM porin OmpA. T. brucei porin (TbPorin) is present as a monomer as well as an oligomer on the mitochondrial OM, and its expression is developmentally regulated. In spite of its distinct structure, the TbPorin function is similar to those of other eukaryotic porins. TbPorin RNA interference (RNAi) reduced cell growth in both procyclic and bloodstream forms. The depletion of TbPorin decreased ATP production by inhibiting metabolite flux through the OM. Additionally, the level of trypanosome alternative oxidase (TAO) decreased, whereas the levels of cytochrome-dependent respiratory complexes III and IV increased in TbPorin-depleted mitochondria. Furthermore, the depletion of TbPorin reduced cellular respiration via TAO, which is not coupled with oxidative phosphorylation, but increased the capacity for cyanide-sensitive respiration. Together, these data reveal that TbPorin knockdown reduced the mitochondrial ATP level, which in turn increased the capacity of the cytochrome-dependent respiratory pathway (CP), in an attempt to compensate for the mitochondrial energy crisis. However, a simultaneous decrease in the substrate-level phosphorylation due to TbPorin RNAi caused growth inhibition in the procyclic form. We also found that the expressions of TAO and CP proteins are coordinately regulated in T. brucei according to mitochondrial energy demand.Trypanosoma brucei belongs to a group of parasitic protozoa that possess a single tubular mitochondrion with a concatenated structure of mitochondrial DNA known as kinetoplast (30). T. brucei is the infectious agent of the disease African trypanosomiasis, which is spread from one mammal to another by the bite of the tsetse fly (53). During transmission from the insect vector to the mammalian host and vice versa, the parasite undergoes various developmental stages accompanied by dramatic changes in mitochondrial activities (15). The bloodstream form that grows in mammalian blood uses glucose as its energy source and suppresses many mitochondrial activities. The bloodstream-form mitochondria lack cytochromes; thus, respiration in this form is solely dependent on the cytochrome-independent trypanosome alternative oxidase (TAO) (15). In contrast, the procyclic form that lives in the insect''s midgut possesses a developed mitochondrion with a full complement of the cytochrome-dependent respiratory system and a reduced level of TAO. The procyclic-form mitochondria produce ATP by both oxidative and substrate-level phosphorylations (7). On the other hand, the bloodstream-form mitochondria do not produce ATP but hydrolyze ATP to maintain the inner membrane (IM) potential (10, 33, 39, 48). Many of the mitochondrial IM- and matrix-localized proteins in T. brucei are well characterized (11, 29, 34, 43, 45). However, the mitochondrial outer membrane (OM) proteins in this group of parasitic protozoa have been poorly explored.Mitochondrial porin, which is also known as the voltage-dependent anion-selective channel (VDAC), is the most abundant protein in the OM (17, 28). The sizes and the secondary structures of this protein are very similar among different organisms. The VDAC possesses a N-terminal α-helical domain, and the rest of the protein consists of a number of amphiphilic β-strands, which form a barrel-like structure that integrates into the lipid bilayer (16, 17, 28). Recently, the three-dimensional structure of the human VDAC has been elucidated by nuclear magnetic resonance spectroscopy and X-ray crystallography, which showed a β-barrel architecture composed of 19 β-strands and the N-terminal α-helix located horizontally midway in the pore (5). Saccharomyces cerevisiae and Neurospora crassa VDACs also possess 16 to 19 β-strands, similar to the mammalian VDAC (17).The VDAC exists as different isomeric forms in different species (16, 19). In yeasts, there are two forms: VDAC1 and VDAC2. Only VDAC1 has the channel activity and is abundantly expressed (22, 23). Animals have three isoforms: VDAC1 to VDAC3. These isoforms showed more than 80% sequence homology among themselves. However, their expression levels and tissue specificities are different (16). Plants also have multiple isoforms of the VDAC with various expression levels under different pathological conditions (19). The VDAC plays a crucial role in regulated transport of ADP, ATP, Ca²⁺, and other metabolites in and out of mitochondria (17, 28, 41). Two ATP-binding sites found at the N- and C-terminal regions in the VDAC are critical for its function (54). Downregulation of VDAC expression disrupts mitochondrial energy production (22, 25). In contrast, overexpression of the VDAC in metazoa induces apoptosis, which can be blocked by compounds that inhibit its channel activity (1, 47).The OM of gram-negative bacteria also consists of various types of porins (24, 32, 40). Based on their structures and functions, they are divided into five groups. OmpA belongs to the small β-barrel integral membrane protein family, which is composed of eight β-strands. It is highly abundant and ubiquitous among most gram-negative bacteria (21). Other types of porins include general porin OmpF, which consists of 16 β-strands; substrate-specific porins, such as LamB or maltoporin, which contains 18 β-strands; receptor-type porin FhuA, the largest β-barrel, with 22 β-strands; and phospholipase A or OMPLA, an integral membrane enzyme containing 12 β-strands (21, 24, 32, 40). The OmpA plays important roles in bacterial conjugation, adhesion, invasion, and immune evasion and also acts as the receptor for several bacteriophages through its surface-exposed loops (44).Here, we show that the T. brucei mitochondrial porin (TbPorin) possesses a predicted β-barrel structure that has fewer β-strands than other mitochondrial porins but is similar to bacterial OmpA. TbPorin is crucial for mitochondrial energy production via both oxidative and substrate-level phosphorylations. The depletion of TbPorin reduced cell growth of the procyclic form as well as the bloodstream form. Furthermore, it reveals that depletion of mitochondrial ATP level by downregulation of porin alters the electron flow via TAO and the cytochrome-dependent pathway (CP) as well as the levels of proteins in these pathways.     

Effect of Foot-and-Mouth Disease Virus Infection on the Frequency,Phenotype and Function of Circulating Dendritic Cells in Cattle

Foot-and-mouth disease virus (FMDV) is a highly contagious virus that causes one of the most devastating diseases in cloven-hoofed animals. Disease symptoms develop within 2 to 3 days of exposure and include fever and vesicular lesions on the tongue and hooves. Dendritic cells (DC) play an essential role in protective immune responses against pathogens. Therefore, investigating their role during FMDV infection would lead to a better understanding of host-pathogen interactions. In this study, following infection of cattle with FMDV, we investigated the frequency and function of conventional (cDC) and plasmacytoid DC (pDC) in blood by using multi-color flow cytometry. We show that the frequency of cDC and pDC increased following FMDV infection and peaked 3 to 4 days post-infection. During peak viremia, the cattle became lymphopenic, the expression of MHC class II molecules on cDC and pDC was dramatically down-regulated, the processing of exogenous antigen by cDC and pDC was impaired, and there was an increase in IL-10 production by DC and monocytes. Notably, after clearance of FMDV from the blood, MHC class II expression returned to pre-infection levels. Altogether, our study demonstrates that in cattle, FMDV inhibits the function of DC, thereby retarding the initiation of adaptive immune responses, potentially enhancing virus shedding during the acute phase of infection.     

Blood Lactate/ATP Ratio,as an Alarm Index and Real-Time Biomarker in Critical Illness

Objective

The acute physiology, age and chronic health evaluation (APACHE) II score and other related scores have been used for evaluation of illness severity in the intensive care unit (ICU), but there is still a need for real-time and sensitive prognostic biomarkers. Recently, alarmins from damaged tissues have been reported as alarm-signaling molecules. Although ATP is a member of the alarmins and its depletion in tissues closely correlates with multiple-organ failure, blood ATP level has not been evaluated in critical illness. To identify real-time prognostic biomarker of critical illness, we measured blood ATP levels and the lactate/ATP ratio (ATP-lactate energy risk score, A-LES) in critically ill patients.

Methods and Results

Blood samples were collected from 42 consecutive critically ill ICU patients and 155 healthy subjects. The prognostic values of blood ATP levels and A-LES were compared with APACHE II score. The mean ATP level (SD) in healthy subjects was 0.62 (0.19) mM with no significant age or gender differences. The median ATP level in severely ill patients at ICU admission was significantly low at 0.31 mM (interquartile range 0.25 to 0.44) than the level in moderately ill patient at 0.56 mM (0.38 to 0.70) (P<0.01). Assessment with ATP was further corrected by lactate and expressed as A-LES. The median A-LES was 2.7 (2.1 to 3.3) in patients with satisfactory outcome at discharge but was significantly higher in non-survivors at 38.9 (21.0 to 67.9) (P<0.01). Receiver operating characteristic analysis indicated that measurement of blood ATP and A-LES at ICU admission are as useful as APACHE II score for prediction of mortality.

Conclusion

Blood ATP levels and A-LES are sensitive prognostic biomarkers of mortality at ICU admission. In addition, A-LES provided further real-time evaluation score of illness severity during ICU stay particularly for critically ill patients with APACHE II scores of ≥20.0.     

Circulating Mitochondrial DNA in Patients in the ICU as a Marker of Mortality: Derivation and Validation

Background

Mitochondrial DNA (mtDNA) is a critical activator of inflammation and the innate immune system. However, mtDNA level has not been tested for its role as a biomarker in the intensive care unit (ICU). We hypothesized that circulating cell-free mtDNA levels would be associated with mortality and improve risk prediction in ICU patients.

Methods and Findings

Analyses of mtDNA levels were performed on blood samples obtained from two prospective observational cohort studies of ICU patients (the Brigham and Women''s Hospital Registry of Critical Illness [BWH RoCI, n = 200] and Molecular Epidemiology of Acute Respiratory Distress Syndrome [ME ARDS, n = 243]). mtDNA levels in plasma were assessed by measuring the copy number of the NADH dehydrogenase 1 gene using quantitative real-time PCR. Medical ICU patients with an elevated mtDNA level (≥3,200 copies/µl plasma) had increased odds of dying within 28 d of ICU admission in both the BWH RoCI (odds ratio [OR] 7.5, 95% CI 3.6–15.8, p = 1×10⁻⁷) and ME ARDS (OR 8.4, 95% CI 2.9–24.2, p = 9×10⁻⁵) cohorts, while no evidence for association was noted in non-medical ICU patients. The addition of an elevated mtDNA level improved the net reclassification index (NRI) of 28-d mortality among medical ICU patients when added to clinical models in both the BWH RoCI (NRI 79%, standard error 14%, p<1×10⁻⁴) and ME ARDS (NRI 55%, standard error 20%, p = 0.007) cohorts. In the BWH RoCI cohort, those with an elevated mtDNA level had an increased risk of death, even in analyses limited to patients with sepsis or acute respiratory distress syndrome. Study limitations include the lack of data elucidating the concise pathological roles of mtDNA in the patients, and the limited numbers of measurements for some of biomarkers.

Conclusions

Increased mtDNA levels are associated with ICU mortality, and inclusion of mtDNA level improves risk prediction in medical ICU patients. Our data suggest that mtDNA could serve as a viable plasma biomarker in medical ICU patients. Please see later in the article for the Editors'' Summary     

NAD+-Dependent Activation of Sirt1 Corrects the Phenotype in a Mouse Model of Mitochondrial Disease

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JARID1B Expression Plays a Critical Role in Chemoresistance and Stem Cell-Like Phenotype of Neuroblastoma Cells

Neuroblastoma (NB) is a common neural crest-derived extracranial solid cancer in children. Among all childhood cancers, NB causes devastating loss of young lives as it accounts for 15% of childhood cancer mortality. Neuroblastoma, especially high-risk stage 4 NB with MYCN amplification has limited treatment options and associated with poor prognosis. This necessitates the need for novel effective therapeutic strategy. JARID1B, also known as KDM5B, is a histone lysine demethylase, identified as an oncogene in many cancer types. Clinical data obtained from freely-accessible databases show a negative correlation between JARID1B expression and survival rates. Here, we demonstrated for the first time the role of JARID1B in the enhancement of stem cell-like activities and drug resistance in NB cells. We showed that JARID1B may be overexpressed in either MYCN amplification (SK-N-BE(2)) or MYCN-non-amplified (SK-N-SH and SK-N-FI) cell lines. JARID1B expression was found enriched in tumor spheres of SK-N-BE(2) and SK-N-DZ. Moreover, SK-N-BE(2) spheroids were more resistant to chemotherapeutics as compared to parental cells. In addition, we demonstrated that JARID1B-silenced cells acquired a decreased propensity for tumor invasion and tumorsphere formation, but increased sensitivity to cisplatin treatment. Mechanistically, reduced JARID1B expression led to the downregulation of Notch/Jagged signaling. Collectively, we provided evidence that JARID1B via modulation of stemness-related signaling is a putative novel therapeutic target for treating malignant NB.     

The Migration Test on Circulating Bovine Leukocytes and its Possible Application in the Diagnosis of Johne's Disease

The leukocyte migration test for in vitro studies of delayed type hypersensitivity has recently been reviewed (Søborg & Ben-dixen 1967; Bendixen & Søborg 1969). Søborg & Bendixen applied the test to circulating leukocytes in man and thereby widely increased the potentialities of this test. They obtained high leukocyte yields with only moderate erythrocyte admixture by harvesting the supernatant plasma after sedimentation of the erythrocytes for 60 min. at 37°C in the normal gravitational field (1 × g)- Their procedure was unsuitable for the present investigation because bovine erythrocytes sediment so slowly. Sedimentation after clumping at the interphase of aqueous solutions of polymers, dextran and methylcellulose, in combination with metrizoic acid (Böyum 1968) was tried without success because the vast majority of the leukocytes sedimented together with the erythrocytes. Separation of leukocytes from erythrocytes could not be achieved by differential centrifugation.