334 research outputs found
Mitochondrial dysfunction in peripheral blood mononuclear cells in pediatric septic shock
OBJECTIVES: Mitochondrial dysfunction in peripheral blood mononuclear cells has been linked to immune dysregulation and organ failure in adult sepsis, but pediatric data are limited. We hypothesized that pediatric septic shock patients exhibit mitochondrial dysfunction within peripheral blood mononuclear cells which in turn correlates with global organ injury. DESIGN: Prospective observational study. SETTING: Academic PICU. PATIENTS: Thirteen pediatric patients with septic shock and greater than or equal to two organ failures and 11 PICU controls without sepsis or organ failure. INTERVENTIONS: Ex vivo measurements of mitochondrial oxygen consumption and membrane potential (DeltaPsim) were performed in intact peripheral blood mononuclear cells on day 1-2 and day 5-7 of septic illness and in controls. The Pediatric Logistic Organ Dysfunction score, inotrope score, and organ failure-free days were determined from medical records. MEASUREMENTS AND MAIN RESULTS: Spare respiratory capacity, an index of bioenergetic reserve, was lower in septic peripheral blood mononuclear cells on day 1-2 (median, 1.81; interquartile range, 0.52-2.09 pmol O2/s/10 cells) compared with controls (5.55; 2.80-7.21; p = 0.03). Spare respiratory capacity normalized by day 5-7. Patients with sepsis on day 1-2 exhibited a higher ratio of LEAK to maximal respiration than controls (17% vs \u3c 1%; p = 0.047) with normalization by day 5-7 (1%; p = 0.008), suggesting mitochondrial uncoupling early in sepsis. However, septic peripheral blood mononuclear cells exhibited no differences in basal or adenosine triphosphate-linked oxygen consumption or DeltaPsim. Oxygen consumption did not correlate with Pediatric Logistic Organ Dysfunction score, inotrope score, or organ failure-free days (all p \u3e 0.05). Although there was a weak overall association between DeltaPsim on day 1-2 and organ failure-free days (Spearman rho = 0.56, p = 0.06), patients with sepsis with normal organ function by day 7 exhibited higher DeltaPsim on day 1-2 compared with patients with organ failure for more than 7 days (p = 0.04). CONCLUSIONS: Mitochondrial dysfunction was present in peripheral blood mononuclear cells in pediatric sepsis, evidenced by decreased bioenergetic reserve and increased uncoupling. Mitochondrial membrane potential, but not respiration, was associated with duration of organ injury
Investigating the interplay between gaming disorder and functional impairments in professional esports gaming
The relationship between Gaming Disorder (GD) and the experience of functional impairments has received considerable theoretical attention in the recent past and current diagnostic approaches underscore the centrality of functional impairments as a requirement for GD diagnosis. However, there is limited empirical evidence illuminating the interplay between GD and functional impairments, particularly among specific vulnerable groups. The present study seeks to bridge this gap by investigating an English-speaking sample (N = 5198) comprising an age- and gender-matched group of Professional Gamers (PG, n = 2599) and Non-Professional Gamers (NPG, n = 2599) sub-sampled from a larger sample of 192,260 individuals. The results revealed that PG were at a greater risk for GD compared to NPG as the prevalence rate of GD among PG (3.31%) was significantly higher and almost doubled that of NPG (1.73%), with PG further exhibiting higher overall GD symptom-load and weekly time spent gaming compared to NPG. Furthermore, PG reported experiencing significantly higher frequency of gaming-related functional impairments compared to NPG, with the in particular affected areas for both PG and NPG being ‘school and/or work’, ‘physical health’, and ‘family’, with other key differences emerging in relation to other outcomes. Overall, the present findings show that not only GD symptom-load but also some functional impairment is higher in PG compared to NPG which highlights the need to develop and support prevention and intervention strategies for this at-risk population
Comprehensive Antigen Screening Identifies Moraxella catarrhalis Proteins That Induce Protection in a Mouse Pulmonary Clearance Model
Moraxella catarrhalis is one of the three most common causative bacterial pathogens of otitis media, however no effective vaccine against M. catarrhalis has been developed so far. To identify M. catarrhalis vaccine candidate antigens, we used carefully selected sera from children with otitis media and healthy individuals to screen small-fragment genomic libraries that are expressed to display frame-selected peptides on a bacterial cell surface. This ANTIGENome technology led to the identification of 214 antigens, 23 of which were selected by in vitro or in vivo studies for additional characterization. Eight of the 23 candidates were tested in a Moraxella mouse pulmonary clearance model, and 3 of these antigens induced significantly faster bacterial clearance compared to adjuvant or to the previously characterized antigen OmpCD. The most significant protection data were obtained with the antigen MCR_1416 (Msp22), which was further investigated for its biological function by in vitro studies suggesting that Msp22 is a heme binding protein. This study comprises one of the most exhaustive studies to identify potential vaccine candidate antigens against the bacterial pathogen M. catarrhalis
Inborn and acquired metabolic defects in cancer
The observation that altered metabolism is the fundamental cause of cancer was made by Otto Warburg nearly a century ago. However, the subsequent identification of oncogenes and tumor suppressor genes has displaced Warburg's theory pointing towards genetic aberrations as the underlining cause of cancer. Nevertheless, in the last decade, cancer-associated mutations have been identified in genes coding for tricarboxylic acid cycle (TCA cycle, also known as Krebs cycle) and closely related enzymes that have essential roles in cellular metabolism. These observations have revived interest in Warburg's hypothesis and prompted a flurry of functional studies in the hope of gaining mechanistic insight into the links between mitochondrial dysfunction, metabolic alterations, and cancer. In this review, we discuss the potential pro-oncogenic signaling role of some TCA cycle metabolites and their derivatives (oncometabolites). In particular, we focus on their effects on dioxygenases, a family of oxygen and α-ketoglutarate-dependent enzymes that control, among other things, the levels and activity of the hypoxia-inducible transcription factors and the activity of DNA and histone demethylases
The role of complex II in disease
AbstractGenetically defined mitochondrial deficiencies that result in the loss of complex II function lead to a range of clinical conditions. An array of tumor syndromes caused by complex II-associated gene mutations, in both succinate dehydrogenase and associated accessory factor genes (SDHA, SDHB, SDHC, SDHD, SDHAF1, SDHAF2), have been identified over the last 12 years and include hereditary paraganglioma–pheochromocytomas, a diverse group of renal cell carcinomas, and a specific subtype of gastrointestinal stromal tumors (GIST). In addition, congenital complex II deficiencies due to inherited homozygous mutations of the catalytic components of complex II (SDHA and SDHB) and the SDHAF1 assembly factor lead to childhood disease including Leigh syndrome, cardiomyopathy and infantile leukodystrophies. The role of complex II subunit gene mutations in tumorigenesis has been the subject of intensive research and these data have led to a variety of compelling hypotheses. Among the most widely researched are the stabilization of hypoxia inducible factor 1 under normoxia, and the generation of reactive oxygen species due to defective succinate:ubiquinone oxidoreductase function. Further progress in understanding the role of complex II in disease, and in the development of new therapeutic approaches, is now being hampered by the lack of relevant cell and animal models. This article is part of a Special Issue entitled: Respiratory complex II: Role in cellular physiology and disease
- …