First two unrelated cases of isolated sedoheptulokinase deficiency: A benign disorder?

We present the first two reported unrelated patients with an isolated sedoheptulokinase (SHPK) deficiency. The first patient presented with neonatal cholestasis, hypoglycemia, and anemia, while the second patient presented with congenital arthrogryposis multiplex, multiple contractures, and dysmorphisms. Both patients had elevated excretion of erythritol and sedoheptulose, and each had a homozygous nonsense mutation in SHPK. SHPK is an enzyme that phosphorylates sedoheptulose to sedoheptulose-7-phosphate, which is an important intermediate of the pentose phosphate pathway. It is questionable whether SHPK deficiency is a causal factor for the clinical phenotypes of our patients. This study illustrates the necessity of extensive functional and clinical workup for interpreting a novel variant, including nonsense variants

Macrophage Glucose-6-Phosphate Dehydrogenase Stimulates Proinflammatory Responses with Oxidative Stress

Glucose-6-phosphate dehydrogenase (G6PD) is a key enzyme that regulates cellular redox potential. In this study, we demonstrate that macrophage G6PD plays an important role in the modulation of proinflammatory responses and oxidative stress. The G6PD levels in macrophages in the adipose tissue of obese animals were elevated, and G6PD mRNA levels positively correlated with those of proinflammatory genes. Lipopolysaccharide (LPS) and free fatty acids, which initiate proinflammatory signals, stimulated macrophage G6PD. Overexpression of macrophage G6PD potentiated the expression of proinflammatory and prooxidative genes responsible for the aggravation of insulin sensitivity in adipocytes. In contrast, when macrophage G6PD was inhibited or suppressed via chemical inhibitors or small interfering RNA (siRNA), respectively, basal and LPS-induced proinflammatory gene expression was attenuated. Furthermore, macrophage G6PD increased activation of the p38 mitogen-activated protein kinase (MAPK) and NF-??B pathways, which may lead to a vicious cycle of oxidative stress and proinflammatory cascade. Together, these data suggest that an abnormal increase of G6PD in macrophages promotes oxidative stress and inflammatory responses in the adipose tissue of obese animals.open5

A Novel Chromone Derivative with Anti-Inflammatory Property via Inhibition of ROS-Dependent Activation of TRAF6-ASK1-p38 Pathway

The p38 MAPK signaling pathway plays a pivotal role in inflammation. Targeting p38 MAPK may be a potential strategy for the treatment of inflammatory diseases. In the present study, we show that a novel chromone derivative, DCO-6, significantly reduced lipopolysaccharide (LPS)-induced production of nitric oxide, IL-1β and IL-6, decreased the levels of iNOS, IL-1β and IL-6 mRNA expression in both RAW264.7 cells and mouse primary peritoneal macrophages, and inhibited LPS-induced activation of p38 MAPK but not of JNK, ERK. Moreover, DCO-6 specifically inhibited TLR4-dependent p38 activation without directly inhibiting its kinase activity. LPS-induced production of intracellular reactive oxygen species (ROS) was remarkably impaired by DCO-6, which disrupted the formation of the TRAF6-ASK1 complex. Administering DCO-6 significantly protected mice from LPS-induced septic shock in parallel with the inhibition of p38 activation and ROS production. Our results indicate that DCO-6 showed anti-inflammatory properties through inhibition of ROS-dependent activation of TRAF6-ASK1-p38 pathway. Blockade of the upstream events required for p38 MAPK action by DCO-6 may provide a new therapeutic option in the treatment of inflammatory diseases

Glucose Availability and AMP-Activated Protein Kinase Link Energy Metabolism and Innate Immunity in the Bovine Endometrium

Defences against the bacteria that usually infect the endometrium of postpartum cattle are impaired when there is metabolic energy stress, leading to endometritis and infertility. The endometrial response to bacteria depends on innate immunity, with recognition of pathogen-associated molecular patterns stimulating inflammation, characterised by secretion of interleukin (IL)-1β, IL-6 and IL-8. How metabolic stress impacts tissue responses to pathogens is unclear, but integration of energy metabolism and innate immunity means that stressing one system might affect the other. Here we tested the hypothesis that homeostatic pathways integrate energy metabolism and innate immunity in bovine endometrial tissue. Glucose deprivation reduced the secretion of IL-1β, IL-6 and IL-8 from ex vivo organ cultures of bovine endometrium challenged with the pathogen-associated molecular patterns lipopolysaccharide and bacterial lipopeptide. Endometrial inflammatory responses to lipopolysaccharide were also reduced by small molecules that activate or inhibit the intracellular sensor of energy, AMP-activated protein kinase (AMPK). However, inhibition of mammalian target of rapamycin, which is a more global metabolic sensor than AMPK, had little effect on inflammation. Similarly, endometrial inflammatory responses to lipopolysaccharide were not affected by insulin-like growth factor-1, which is an endocrine regulator of metabolism. Interestingly, the inflammatory responses to lipopolysaccharide increased endometrial glucose consumption and induced the Warburg effect, which could exacerbate deficits in glucose availability in the tissue. In conclusion, metabolic energy stress perturbed inflammatory responses to pathogen-associated molecular patterns in bovine endometrial tissue, and the most fundamental regulators of cellular energy, glucose availability and AMPK, had the greatest impact on innate immunity

BCAT1 controls metabolic reprogramming in activated human macrophages and is associated with inflammatory diseases

This work was supported by the Medical Research Council (MR/M004716/1 and MR/N01121X/1 to J.B.) and by Kidney Research UK (RP9/2013 to J.B.). D.C. is supported by the Institute Pasteur, Fondazione Cenci Bolognetti. C.M. is supported by the British Hearth Foundation Fellowship (FS/12/3829640)

Surgical Management of Infective Endocarditis: Early and Long-Term Mortality Analysis. Single-Center Experience and Brief Literature Review

Introduction: In this study we evaluated factors that affect the early and long-term postoperative outcomes of patients with infective endocarditis. Methods: We retrospectively reviewed 94 patients (68 male, 26 female, mean age 58.3 +/- 13.1 years, range 20-85 years) with proven infective native (n=85) or prosthetic valve (n=9) endocarditis who underwent heart valve surgery between September 1997 and December 2007. Fifty-four patients (57.4%) underwent aortic, 28 (29.8%) mitral, 3 (3.2%) tricuspid, 8 (8.5%) double, and one patient (1%) triple valve surgery. In 75.5% of the procedures we implanted mechanical valves, in 13.8% biological prostheses, and 10.7% were reconstructive or other procedures. Midterm follow up was 100% complete with a cumulative duration of 545 patient-years (maximum 12 years). Results: Overall hospital mortality (30 days) was 8.5% (n=8). Causes of early mortality were low cardiac output syndrome in 2 cases, sepsis with multiple organ failure in 5 cases, and intracerebral bleeding in one patient. Development of postoperative low cardiac output syndrome (p=0.01) was identified as an independent predictor of early mortality. Overall late mortality was 25.6% (n=22) with a cumulative rate of 4.03% per patient-year. Causes of late death were predominantly of extracardiac origin. Kaplan-Meier survival analysis revealed a cumulative survival rate at 12 years of 57.2%. Cox regression analysis identified diabetes mellitus (p=0.016) and postoperative low cardiac output syndrome (p=0.03) as independent late mortality factors. Conclusions: Heart valve surgery in patients with infective endocarditis is associated with increased but acceptable early and long-term mortality. The mid-term prognosis is similar to that of patients undergoing elective valve replacement surgery

Performance of EuroSCORE II compared to EuroSCORE I in predicting operative and mid-term mortality of patients from a single center after combined coronary artery bypass grafting and aortic valve replacement

Objective: The performance comparison of the recently introduced European System for Cardiac Operative Risk Evaluation II in predicting operative as well as mid-term mortality, with its previous version in patients after combined aortic valve replacement and coronary artery bypass grafting surgery. Methods: This retrospective analysis included 216 patients operated on at one institution from 01/1999 to 12/2005. Accuracy and calibration of EuroSCORE I and II were assessed by plotting the areas under the receiver operator curves and comparing observed and predicted mortalities. Results: EuroSCORE II showed, regarding early mortality, a slightly higher discriminatory accuracy with an area under the receiver operator curve of 0.77, while additive and logistic EuroSCORE I areas were 0.749, 0.75, respectively. The highest specificity and sensitivity level was approached for EuroSCORE II at a predicted mortality of 4.4 %. Receiver operator curves concerning mid-term mortality revealed areas for additive, logistic EuroSCORE and EuroSCORE II of 0.745, 0.739 and 0.718 with the highest accuracy levels at predicted mortalities of 6.5, 6.48 and 3.88 %, respectively. Mean predicted mortalities by logistic EuroSCORE and EuroSCORE II were 8.35 and 3.99 %, respectively, while overall observed operative mortality was 6.3 %. In "high-risk" patients (EuroSCORE > 13), EuroSCORE II underestimated early and mid-term outcomes. Conclusions: Regarding operative mortality, EuroSCORE II showed in this study a slightly higher discriminatory accuracy than EuroSCORE I. There were no significant differences in the calibration of the two model versions in "low-" and "moderate-risk" patients regarding early as well as mid-term mortality. Analyses in larger patient populations will contribute to further model improvement. © 2013 The Japanese Association for Thoracic Surgery