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Sepsis: The critical role of iron
Abstract
Sepsis is a global problem which is exacerbated by increasing bacterial resistance to antibiotics. However, mechanisms of natural resistance can be extremely effective, and need to be exploited, but the availability of iron is critical for controlling bacterial growth. The diagnosis of sepsis and possible strategies for limiting iron availability are discussed.
... [3][4][5][6] Hemolysis with release of plasma cell-free Hb (CFH) and the resultant nitric oxide (NO) scavenging, vasoconstriction, and vascular injury, [7][8][9] as well as release of RBC iron promoting bacterial growth, have been implicated among the possible mechanisms for the reported toxicity of older stored blood. [10][11][12][13] A recent meta-analysis has further raised concern that patients receiving older blood have increased mortality rates. 14 Four randomized controlled trials addressing this issue are being conducted in Canada, 15,16 Australia, 17 and the United States, 18 but the results may not be available for several years. ...
... However, with increasing doses of bacterial challenge, both iron values decline more rapidly and completely over time with older blood, and their disappearance from the plasma is associated with greater clinical de-compensation and increased mortality. The bacterial dose effect suggests that plasma iron released from RBCs is potentially available to be utilized by the bacteria to promote growth and worsen infection 12,13,19 and, along with NO depletion, 7-9 contributes to clinical effects of the storage lesion. 5,10,11 MATERIALS AND METHODS (Please see online supplement for more complete Materials and Methods) ...
... Further, after transfusion, elevations of iron in the form of NTBI and TBI are available and potentially utilized by bacteria to enhance growth. 13,37,41,42,45 In patients with sepsis, elevated CFH levels are independently associated with an increased risk of death, 47 and critically ill patients, including those with sepsis or at risk for sepsis, have increased levels of CFH. 48 This CFH elevation during sepsis could be related to in vivo hemolysis caused by the infecting bacteria producing hemolysis and accumulating extracellular iron. ...
In experimental pneumonia we found that transfused older blood increased mortality and lung injury that was associated with increased in vivo hemolysis and elevated plasma cell-free hemoglobin (CFH), non-transferrin-bound iron (NTBI), and plasma labile iron (PLI) levels. In this study, we additionally analyze identically treated animals that received lower or higher bacterial doses.
Two-year-old purpose-bred beagles (n = 48) challenged intrabronchially with Staphylococcus aureus (0 [n = 8], 1.0 × 10(9) [n = 8], 1.25 × 10(9) [n = 24], and ≥1.5 × 10(9) [n = 8] colony-forming units/kg) were exchange transfused with either 7- or 42-day-old canine universal donor blood (80 mL/kg in four divided doses).
The greater increases in CFH with older blood over days after exchange proved relatively independent of bacterial dose. The lesser increases in CFH observed with fresher blood were bacterial dose dependent potentially related to bacterial hemolysins. Without bacterial challenge, levels of CFH, NTBI, and PLI were significantly higher with older versus fresher blood transfusion but there was no significant measurable injury. With higher-dose bacterial challenge, the elevated NTBI and PLI levels declined more rapidly and to a greater extent after transfusion with older versus fresher blood, and older blood was associated with significantly worse shock, lung injury, and mortality.
The augmented in vivo hemolysis of transfused older red blood cells (RBCs) appears to result in excess plasma CFH and iron release, which requires the presence of established infection to worsen outcome. These data suggest that transfused older RBCs increase the risks from infection in septic subjects.
... Since about 1970, 6 the biochemical connections between pro-and eukaryotic iron homeostasis were apparent, and many researchers, but especially J. J. Bullen,4,8,75,76 noted the relationship between bacterial iron acquisition and infection. Fifty years of research on these systems confirmed that bacteria need iron for metabolism, they produce biosynthetic and transport systems to obtain it, and their success toward this end influences the outcome of their infections. ...
... 73,88,102−120 • Microbial iron scavenging and host iron sequestration are antagonistic processes that influence infection. 4,7,75,121 • Iron sequestration reduces or eliminates bacterial virulence. 35,82−89,122−131 • Successful pathogens capture iron from their hosts. ...
Iron is an indispensable metabolic cofactor in both pro- and eukaryotes, which engenders a natural competition for the metal between bacterial pathogens and their human or animal hosts. Bacteria secrete siderophores that extract Fe3+ from tissues, fluids, cells, and proteins; the ligand gated porins of the Gram-negative bacterial outer membrane actively acquire the resulting ferric siderophores, as well as other iron-containing molecules like heme. Conversely, eukaryotic hosts combat bacterial iron scavenging by sequestering Fe3+ in binding proteins and ferritin. The variety of iron uptake systems in Gram-negative bacterial pathogens illustrates a range of chemical and biochemical mechanisms that facilitate microbial pathogenesis. This document attempts to summarize and understand these processes, to guide discovery of immunological or chemical interventions that may thwart infectious disease.
... It has been demonstrated in this study that treatment with an antibiotic in combination with DFX improves survival rate these findings are in agreement with the findings of (Yoo et al., 1999) [33] . The study has also demonstrated the beneficial effect of DFX as a supplement to antibiotics, in the survival rate of peritonitis in group A and B: these findings are also in agreement with the findings of (Bullen et al., 2000) [34] . DFX in combination with antibiotics have a significant effect on survival rates when compared with the survival rate of dogs treated with DFX alone. ...
... It has been demonstrated in this study that treatment with an antibiotic in combination with DFX improves survival rate these findings are in agreement with the findings of (Yoo et al., 1999) [33] . The study has also demonstrated the beneficial effect of DFX as a supplement to antibiotics, in the survival rate of peritonitis in group A and B: these findings are also in agreement with the findings of (Bullen et al., 2000) [34] . DFX in combination with antibiotics have a significant effect on survival rates when compared with the survival rate of dogs treated with DFX alone. ...
The present study was conducted to evaluate the therapeutic efficacy of deferoxamine (DFX) as an adjunct to rational therapy alone or in combination with vitamin C in induced endotoxemia in a dog model in 2013 A total of 18 adult, healthy dogs of either sex were randomly selected and divided into three equal groups viz. A, B and C. All above parameters were recorded at baseline, during septic shock, 3, 6, 12 and 24 hrs after treatment. Survival index of one week was also recorded. Group A and group B showed better survival rate of 83% than group C (66 %). The body temperature was elevated during shock in all groups but both A and B group attained the baseline value. As also was the case with the other clinical parameters. The haemoglobin concentration, RBCs count, neutrophils and lymphocytes were at lower level during shock in all groups and attained the baseline values 24-hour post treatment. Animals of group A (treated with DFX along with antibiotic and vitamin C) as well as group B (dosed with DFX & antibiotics showed better results than group C which received DFX without antibiotics and vitamin C. It was concluded that the DFX along with antibiotics can combat the septic shock and resulted in early and better recovery.
... We used TIS to identify genes involved in resistance to the multiple heat sensitive (i.e. complement proteins) and heat stable (nutritional constraint) anti-bacterial factors present in HS 36 . First, we optimized screening conditions by generating a mutant unable to synthesize capsular polysaccharides by in-frame deletion. ...
... While many heat-labile components of HS are directly bactericidal, the nutrient content of HS also imposes a restriction on bacterial growth 36 . We hypothesized that many of the mutants found to be similarly attenuated in the HS and hiHS screens had a reduced capacity to overcome the nutritional constraints of HS (Table S9). ...
Vibrio vulnificus can be a highly invasive pathogen capable of spreading from an infection site to the bloodstream, causing sepsis and death. To survive and proliferate in blood, the pathogen requires mechanisms to overcome the innate immune defenses and metabolic limitations of this host niche. We created a high-density transposon mutant library in YJ016, a strain representative of the most virulent V. vulnificus lineage (or phylogroup) and used transposon insertion sequencing (TIS) screens to identify loci that enable the pathogen to survive and proliferate in human serum. Initially, genes underrepresented for insertions were used to estimate the V. vulnificus essential gene set; comparisons of these genes with similar TIS-based classification of underrepresented genes in other vibrios enabled the compilation of a common Vibrio essential gene set. Analysis of the relative abundance of insertion mutants in the library after exposure to serum suggested that genes involved in capsule biogenesis are critical for YJ016 complement resistance. Notably, homologues of two genes required for YJ016 serum-resistance and capsule biogenesis were not previously linked to capsule biogenesis and are largely absent from other V. vulnificus strains. The relative abundance of mutants after exposure to heat inactivated serum was compared with the findings from the serum screen. These comparisons suggest that in both conditions the pathogen relies on its Na⁺ transporting NADH-ubiquinone reductase (NQR) complex and type II secretion system to survive/proliferate within the metabolic constraints of serum. Collectively, our findings reveal the potency of comparative TIS screens to provide knowledge of how a pathogen overcomes the diverse limitations to growth imposed by serum.
... Specifically, interleukin (IL)-6 and other cytokines activate the signal transducer and activator of transcription 3 (Stat3) pathway thereby upregulating hepcidin expression and reducing free Fe (Recalcati et al., 2012;Ruchala and Nemeth, 2014). This hepcidin pathway is likely an important component of newborn host defence, as human neonatal plasma Fe levels directly correlate with susceptibility to sepsis (Bullen et al., 2000;Johnson and Wessling-Resnick, 2012;Nairz et al., 2014;Oppenheimer, 2012;Wander et al., 2009). Specifically, a dramatic physiological drop in serum Fe within hours of birth reduces the risk for neonatal sepsis (Bullen et al., 2000;Hay et al., 2007;Recalcati et al., 2012;Sturgeon, 1954;Szabó et al., 2001). ...
... This hepcidin pathway is likely an important component of newborn host defence, as human neonatal plasma Fe levels directly correlate with susceptibility to sepsis (Bullen et al., 2000;Johnson and Wessling-Resnick, 2012;Nairz et al., 2014;Oppenheimer, 2012;Wander et al., 2009). Specifically, a dramatic physiological drop in serum Fe within hours of birth reduces the risk for neonatal sepsis (Bullen et al., 2000;Hay et al., 2007;Recalcati et al., 2012;Sturgeon, 1954;Szabó et al., 2001). Conversely, supplemental Fe given to Fe-replete infants increases the risk for sepsis and death (Oppenheimer, 2012;Oppenheimer, 2001;Sazawal et al., 2006). ...
Infections in the first year of life are common and often severe. The newborn host demonstrates both quantitative and qualitative differences to the adult in nearly all aspects of immunity, which at least partially explain the increased susceptibility to infection. Here we discuss how differences in susceptibility to infection result not out of a state of immaturity, but rather reflect adaptation to the particular demands placed on the immune system in early life. We review the mechanisms underlying host defense in the very young, and discuss how specific developmental demands increase the risk of particular infectious diseases. In this context, we discuss how this plasticity, i.e. the capacity to adapt to demands encountered in early life, also provides the potential to leverage protection of the young against infection and disease through a number of interventions.
... Recent papers suggest heme may play a central role in the pathogenesis of sepsis, stressing the relevance of this finding [55]. In fact, plasma heme has been shown to increase tissue damage in sepsis, promote microbial growth, and sensitize cells to programmed cell death under proinflammatory conditions [55][56][57]. ...
Background:
The association of ageing with increased sepsis mortality is well established. Nonetheless, current investigations on the influence of age on host response aberrations are largely limited to plasma cytokine levels while neglecting other pathophysiological sepsis domains like endothelial cell activation and function, and coagulation activation. The primary objective of this study was to gain insight into the association of ageing with aberrations in key host response pathways and blood transcriptomes in sepsis.
Methods:
We analysed the clinical outcome (n = 1952), 16 plasma biomarkers providing insight in deregulation of specific pathophysiological domains (n = 899), and blood leukocyte transcriptomes (n = 488) of sepsis patients stratified according to age decades. Blood transcriptome results were validated in an independent sepsis cohort and compared with healthy individuals.
Results:
Older age was associated with increased mortality independent of comorbidities and disease severity. Ageing was associated with lower endothelial cell activation and dysfunction, and similar inflammation and coagulation activation, despite higher disease severity scores. Blood leukocytes of patients ≥ 70 years, compared to patients < 50 years, showed decreased expression of genes involved in cytokine signaling, and innate and adaptive immunity, and increased expression of genes involved in hemostasis and endothelial cell activation. The diminished expression of gene pathways related to innate immunity and cytokine signaling in subjects ≥ 70 years was sepsis-induced, as healthy subjects ≥ 70 years showed enhanced expression of these pathways compared to healthy individuals < 50 years.
Conclusions:
This study provides novel evidence that older age is associated with relatively mitigated sepsis-induced endothelial cell activation and dysfunction, and a blood leukocyte transcriptome signature indicating impaired innate immune and cytokine signaling. These data suggest that age should be considered in patient selection in future sepsis trials targeting the immune system and/or the endothelial cell response.
... Particularly pathogenic strains grow well in hemerich conditions, due to their efficient heme capturing ability [68]. Many enteric gram-negative bacteria, including Salmonella, Shigella, and pathogenic E. coli require iron for their virulence and colonization [69,70]. Beneficial commensal gut bacteria from genera Lactobacillus and Bifidobacterium on the other hand require less or no iron [71]. ...
A healthy gut microbiota not only has beneficial effects on the activity of the immune system, but also on thyroid function. Thyroid and intestinal diseases prevalently coexist—Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are the most common autoimmune thyroid diseases (AITD) and often co-occur with Celiac Disease (CD) and Non-celiac wheat sensitivity (NCWS). This can be explained by the damaged intestinal barrier and the following increase of intestinal permeability, allowing antigens to pass more easily and activate the immune system or cross-react with extraintestinal tissues, respectively. Dysbiosis has not only been found in AITDs, but has also been reported in thyroid carcinoma, in which an increased number of carcinogenic and inflammatory bacterial strains were observed. Additionally, the composition of the gut microbiota has an influence on the availability of essential micronutrients for the thyroid gland. Iodine, iron, and copper are crucial for thyroid hormone synthesis, selenium and zinc are needed for converting T4 to T3, and vitamin D assists in regulating the immune response. Those micronutrients are often found to be deficient in AITDs, resulting in malfunctioning of the thyroid. Bariatric surgery can lead to an inadequate absorption of these nutrients and further implicates changes in thyroid stimulating hormone (TSH) and T3 levels. Supplementation of probiotics showed beneficial effects on thyroid hormones and thyroid function in general. A literature research was performed to examine the interplay between gut microbiota and thyroid disorders that should be considered when treating patients suffering from thyroid diseases. Multifactorial therapeutic and preventive management strategies could be established and more specifically adjusted to patients, depending on their gut bacteria composition. Future well-powered human studies are warranted to evaluate the impact of alterations in gut microbiota on thyroid function and diseases.
... More recently, the profound modulatory effects of iron availability on gut microbiome composition and function have been demonstrated [139,140], with implications for metabolic substrate production [139,140] and risk of infection by enteropathogens in young children with ID. Indeed, just as iron is essential for eukaryotic cell function, most bacterial species depend on iron for survival and pathogenicity [141][142][143], and as such, availability of iron may play an important role in microbiome niche selection. ...
Background:
Early-life malnutrition may have long-lasting effects on microbe-host interactions that affect health and disease susceptibility later in life. Diet quality and quantity in conjunction with toxin and pathogen exposure are key contributors to microbe-host physiology and malnutrition. Consequently, it is important to consider both diet- and microbe-induced pathologies as well as their interactions underlying malnutrition.
Main body:
Gastrointestinal immunity and digestive function are vital to maintain a symbiotic relationship between the host and microbiota. Childhood malnutrition can be impacted by numerous factors including gestational malnutrition, early life antibiotic use, psychological stress, food allergy, hygiene, and exposure to other chemicals and pollutants. These factors can contribute to reoccurring environmental enteropathy, a condition characterized by the expansion of commensal pathobionts and environmental pathogens. Reoccurring intestinal dysfunction, particularly during the critical window of development, may be a consequence of diet-microbe interactions and may lead to life-long immune and metabolic programming and increased disease risk. We provide an overview of the some key factors implicated in the progression of malnutrition (protein, fat, carbohydrate, iron, vitamin D, and vitamin B12) and discuss the microbiota during early life that may contribute health risk later in life.
Conclusion:
Identifying key microbe-host interactions, particularly those associated with diet and malnutrition requires well-controlled dietary studies. Furthering our understanding of diet-microbe-host interactions will help to provide better strategies during gestation and early life to promote health later in life.
... However, fetal skin and the mucosal layers produce high levels of antimicrobial proteins and peptides (APPs) such as defensins, lactoferrin, lysozyme, and cathelicidins, which limit infection [82][83][84]. Moreover, serum levels of hepcidin, which reduce free iron, are high at birth thereby limiting bacterial growth and reducing the risk for neonatal sepsis [85,86]. ...
Maternal pregravid obesity results in several adverse health outcomes during pregnancy, including increased risk of gestational diabetes, preeclampsia, placental abruption, and complications at delivery. Additionally, pregravid obesity and in utero exposure to high fat diet have been shown to have detrimental effects on fetal programming, predisposing the offspring to adverse cardiometabolic, endocrine, and neurodevelopmental outcomes. More recently, a deeper appreciation for the modulation of offspring immunity and infectious disease‐related outcomes by maternal pregravid obesity has emerged. This review will describe currently available animal models for studying the impact of maternal pregravid obesity on fetal immunity and review the data from clinical and animal model studies. We also examine the burden of pregravid obesity on the maternal–fetal interface and the link between placental and systemic inflammation. Finally, we discuss future studies needed to identify key mechanistic underpinnings that link maternal inflammatory changes and fetal cellular reprogramming events. Review on the burden of maternal obesity on fetal and maternal immunity.
... Most enteric gram-negative pathogens, including E. coli (Naikare, Palyada, Panciera, Marlow, & Stintzi, 2006), take up iron siderophore complexes via specific outer membrane receptors. In vitro, enteric bacteria display increased virulence in situations of increased Fe availability (Bullen, Griffiths, Rogers, & Ward, 2000). Thus, it is possible that more soluble forms of iron, such as ferrous sulfate, could have a greater effect on enteropathogen growth (Zimmermann et al., 2010). ...
... Free radicals can provoke damage to proteins, nucleic acids, and membrane lipids. Elevated cellular levels of reactive oxygen species have been associated with many age-related health problems including neurodegenerative diseases, malignancy, arthrosclerosis, and heart diseases (1,2) as well as other pathophysiological conditions such as diabetes, ischemia/reperfusion injury (1), sepsis (3) and some complications during pregnancy (4). ...
Using electron paramagnetic resonance (EPR) spectroscopy, antioxidant properties of
chestnut extracts have been investigated as a source of phenolic compounds. In addition
to their high antioxidant activities against hydroxyl and organic free (DPPH) radicals, phenolics
showed to be potent protectors of membranes from lipid peroxidation. To the best
of our knowledge, the ability of an antioxidant to overcome body’s refractory response towards
antioxidant supplementation has been examined for the first time. The water soluble
extracts obtained from leaves, catkins, and outer brown peel of Castanea sativa Mill.
showed high antioxidant activity in scavenging ·OH and DPPH radical. All extracts, except
for sweet chestnut catkins, showed the ability to protect liposomes from peroxidation. Phenolic
compounds, as active antioxidants, have the ability to enter and protect cell membranes
from lipid peroxidation, thus overcoming the body’s refractory response to the antioxidant
supplements in the diet. It is shown that phenolics are easily accessible natural antioxidants
that can be used as food supplements or for the treatment of pathophysiological
conditions related to oxidative stress.
... Free radicals can provoke damage to proteins, nucleic acids, and membrane lipids. Elevated cellular levels of reactive oxygen species have been associated with many age-related health problems including neurodegenerative diseases, malignancy, arthrosclerosis, and heart diseases (1,2) as well as other pathophysiological conditions such as diabetes, ischemia/reperfusion injury (1), sepsis (3) and some complications during pregnancy (4). ...
Using electron paramagnetic resonance (EPR) spectroscopy, antioxidant properties of
chestnut extracts have been investigated as a source of phenolic compounds. In addition
to their high antioxidant activities against hydroxyl and organic free (DPPH) radicals, phenolics
showed to be potent protectors of membranes from lipid peroxidation. To the best
of our knowledge, the ability of an antioxidant to overcome body’s refractory response towards
antioxidant supplementation has been examined for the first time. The water soluble
extracts obtained from leaves, catkins, and outer brown peel of Castanea sativa Mill.
showed high antioxidant activity in scavenging ·OH and DPPH radical. All extracts, except
for sweet chestnut catkins, showed the ability to protect liposomes from peroxidation. Phenolic
compounds, as active antioxidants, have the ability to enter and protect cell membranes
from lipid peroxidation, thus overcoming the body’s refractory response to the antioxidant
supplements in the diet. It is shown that phenolics are easily accessible natural antioxidants
that can be used as food supplements or for the treatment of pathophysiological
conditions related to oxidative stress.
... Although no differences were observed in either C-reactive protein or DNA oxidative damage levels, between patients taking or not the supplement, our results are in agreement with those associating frequent intravenous iron dosing with higher risk of infectious deaths (Collins et al., 1997). It must be remembered that iron is a growth factor for many bacteria, enhancing their proliferation (Bullen et al., 2000), and also could diminish neutrophil migration, impairing host defenses (Sengoelge et al., 2003). Thus, when intravenous iron is administered, and the mechanisms of defense of the organism are compromised, this could lead to a sepsis. ...
End-stage renal disease (ESRD) patients present high levels of phosphorus and calcium products in serum, which contribute to the development of vascular calcification and cardiovascular disease, and to low iron stores and carnitine deficiency. For these reasons, ESRD patients are generally supplemented with different medicines. Some of the most common treatments include the use of Carnicor, Venofer, and Sevelamer drugs. Carnicor is used as a source of L-carnitine, acting as antioxidant and neuroprotector. Venofer is used to reduce the deficit of iron. Sevelamer is used to treat hyperphosphatemia. To determine the potential harmful genotoxic effects of these drugs, a group of 214 patients included in a hemodialysis program with different intakes of Carnicor, Venofer, and Sevelamer were evaluated. The levels of basal and oxidative DNA damage, as well as chromosomal damage, were measured in all individuals using the comet and the micronucleus assays, respectively. Our results indicate that Carnicor administration was associated with low but significant increases in the frequency of basal DNA damage and micronuclei. Environ. Mol. Mutagen., 2018. © 2018 Wiley Periodicals, Inc.
... Iron is an essential and often growth-limiting nutrient for many gut bacteria (24). For many enteric gram-negative bacteria (e.g., Salmonella, Shigella, and pathogenic Escherichia coli), iron acquisition is critical for virulence and colonization (24)(25)(26). In contrast, beneficial commensal gut bacteria from the genera Lactobacillus and Bifidobacterium require little or no iron (27) and reduce growth and colonization by enteric pathogens (28,29). ...
In infants and young children in Sub-Saharan Africa, iron-deficiency anemia (IDA) is common, and many complementary foods are low in bioavailable iron. In-home fortification of complementary foods using iron-containing micronutrient powders (MNPs) and oral iron supplementation are both effective strategies to increase iron intakes and reduce IDA at this age. However, these interventions produce large increases in colonic iron because the absorption of their high iron dose (≥12.5 mg) is typically <20%. We reviewed studies in infants and young children on the effects of iron supplements and iron fortification with MNPs on the gut microbiome and diarrhea. Iron-containing MNPs and iron supplements can modestly increase diarrhea risk, and in vitro and in vivo studies have suggested that this occurs because increases in colonic iron adversely affect the gut microbiome in that they decrease abundances of beneficial barrier commensal gut bacteria (e.g., bifidobacteria and lactobacilli) and increase the abundance of enterobacteria including entropathogenic Escherichia coli These changes are associated with increased gut inflammation. Therefore, safer formulations of iron-containing supplements and MNPs are needed. To improve MNP safety, the iron dose of these formulations should be reduced while maximizing absorption to retain efficacy. Also, the addition of prebiotics to MNPs is a promising approach to mitigate the adverse effects of iron on the infant gut.
... Microbes must acquire iron during colonization of humans and animals (25), and the ubiquitous TonB-dependent iron uptake systems of Gram-negative bacteria are virulence determinants (56,57). The spectroscopic methodology we developed to study TonB-dependent transport, and customized for FLHTS, allows facile discovery of chemicals that may block or impair TonB action; these may become antibacterial drugs. ...
Gram-negative bacteria acquire ferric siderophores through TonBdependent outer membrane transporters (TBDT). By fluorescence spectroscopic hghthroughput screening (FLHTS), we identified inhibitors of TonB-dependent ferric enterobactin (FeEnt) uptake through Escherichia coli FepA (EcoFepA). Among 165 inhibitors found in a primary screen of 17,441 compounds, we evaluated 20 in secondary tests: TonB-dependent ferric siderophore uptake and colicin killing and proton motive force-dependent lactose transport. Six of 20 primary hits inhibited TonBdependent activity in all tests. Comparison of their effects on [⁵⁹Fe]Ent and [¹⁴C]lactose accumulation suggested several as proton ionophores, but two chemicals, ebselen and ST0082990, are likely not proton ionophores and may inhibit TonBExbBD. The facility of FLHTS against E. coli led us to adapt it to Acinetobacter baumannii. We identified its FepA ortholog (AbaFepA), deleted and cloned its structural gene, genetically engineered 8 Cys substitutions in its surface loops, labeled them with fluorescein, and made fluorescence spectroscopic observations of FeEnt uptake in A. baumannii. Several Cys substitutions in AbaFepA (S279C, T562C, and S665C) were readily fluoresceinated and then suitable as sensors of FeEnt transport. As in E. coli, the test monitored TonB-dependent FeEnt uptake by AbaFepA. In microtiter format with A. baumannii, FLHTS produced Z= factors 0.6 to 0.8. These data validated the FLHTS strategy against even distantly related Gram-negative bacterial pathogens. Overall, it discovered agents that block TonB-dependent transport and showed the potential to find compounds that act against Gram-negative CRE (carbapenemresistant Enterobacteriaceae)/ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) pathogens. Our results suggest that hundreds of such chemicals may exist in larger compound libraries.
... Iron is an essential, growth-limiting nutrient for many gut bacteria, competing for unabsorbed dietary iron [42]. For most enteric gram-negative bacteria (e.g., Salmonella, Shigella or pathogenic Escherichia coli), iron acquisition plays an essential role in virulence and colonization [43,44]. Commensal gut bacteria belonging to the genera Lactobacillus and Bifidobacterium provide an important 'barrier effect' against colonization by pathogens [45], and in contrast to most enteric gram-negative bacteria, lactobacilli do not require iron, but instead rely on manganese [46]. ...
Iron deficiency anemia (IDA) is common among infants and children in Sub-Saharan Africa and is a leading contributor to the global burden of disease, as well as a hindrance to national development. In-home iron fortification of complementary foods using micronutrient powders (MNPs) effectively reduces the risk for IDA by ensuring that the iron needs of infants and young children are met without changing their traditional diet. However, the iron dose delivered by MNPs is high, and comparable on a mg iron per kg body weight to the supplemental doses (2 mg/kg) typically given to older children, which increases diarrhea risk. In controlled studies, iron-containing MNPs modestly increase risk for diarrhea in infants; in some cases, the diarrhea is severe and may require hospitalization. Recent in vitro and in vivo studies provide insights into the mechanism of this effect. Provision of iron fortificants to school-age children and iron-containing MNPs to weaning infants decreases the number of beneficial 'barrier' commensal gut bacteria (e.g., bifidobacteria), increases the enterobacteria to bifidobacteria ratio and abundances of opportunistic pathogens (e.g., pathogenic Escherichia coli), and induces gut inflammation. Thus, although iron-containing MNPs are highly effective in reducing IDA, they may increase gastrointestinal morbidity in infants, and safer formulations are needed.
... The delicate balance between the advantageous and detrimental effects of free radicals is clearly an important aspect of life. While the controlled production of reactive oxygen species has an important role in various physiological processes such as different receptor-mediated signaling pathways, immune response, programmed cell death, plant growth etc. [37], enhanced generation of radicals appears to be highly correlated with many pathophysiological events such as neurodegenerative diseases (Alzheimer disease, Amyotrophic lateral sclerosis, Down's syndrome), malignancy, diabetes mellitus, arthrosclerosis, ageing [37], and sepsis [37,38]. Therefore, to have an internal understanding of biosystems, it is important to investigate and quantify the production of radicals and to understand mechanisms through which reactive species are generated and through which they affect cells, tissues and the functioning of organisms. ...
... Free heme has been studied as a key inflammatory mediator of sepsis that acts through the mechanism of oxidative reaction and/or other unknown mechanisms. Free heme in plasma increases morbidity and/or mortality by amplifying inflammatory reactions [23]. Moreover, free heme is especially cytotoxic when present together with proinflammatory cytokines such as TNF-α and IL-6, and free heme was reported to accelerate proinflammatory TLR expression and provide iron as a nutrient to bacteria [6,10]. ...
... [3][4][5][6][7][8] This signalling is involved in the regulation of vascular tone, oxygen tension, activity of the immune system, growth in plants, and some other physiological processes. 9 On the other han d, uncontrolled generation of radicals is highl y related to many pathophysiological events, such as neurodegenerative diseas es (Alzheimer's disease, amyotrophic lateral sclerosis, Down's syndrome, etc), [10][11][12][13] malignancy, 14 diabetes mellitus, 15 sepsis 16 and atherosclerosis, 17 and also see ms to play an important role in the aging process. 1,2,18,19 Hence, a certain level of oxidation performed by free radicals is mandatory in biosystems, but increased oxidation may jeopardize norm al functioning and lead to patho physiological conditions. ...
In this era of intense study of free radicals and antioxidants, electron paramagnetic resonance (EPR) is arguably the best-suited technique for such research, particularly when considering biochemical and biological systems. No attempt was made to cover all the topics of EPR application but instead attention was restricted to two areas that are both novel and received less attention in previous reviews. In the first section, the application of EPR in assessing the oxidative status of various biological systems, using endogenous stabile paramagnetic species, such as the ascorbyl radical, semiquinone, melanin, and oxidized pigments, is addressed. The second section covers the use of EPR in the emerging field of antioxidant development, using EPR spin-trapping and spin-probing techniques. In both sections, in addition to giving an overview of the available literature, examples (mostly from the authors' recent work) are also presented in sufficient detail to illustrate how to explore the full potential of EPR. This review aims at encouraging biologists, chemists and pharmacologists interested in the redox metabolism of living systems, free radical chemistry or antioxidative properties of new drugs and natural products to take advantage of this technique for their investigations.
... [3][4][5][6][7][8] This signalling is involved in the regulation of vascular tone, oxygen tension, activity of the immune system, growth in plants, and some other physiological processes. 9 On the other han d, uncontrolled generation of radicals is highl y related to many pathophysiological events, such as neurodegenerative diseas es (Alzheimer's disease, amyotrophic lateral sclerosis, Down's syndrome, etc), [10][11][12][13] malignancy, 14 diabetes mellitus, 15 sepsis 16 and atherosclerosis, 17 and also see ms to play an important role in the aging process. 1,2,18,19 Hence, a certain level of oxidation performed by free radicals is mandatory in biosystems, but increased oxidation may jeopardize norm al functioning and lead to patho physiological conditions. ...
Cited By (since 1996):3, Export Date: 18 October 2014
... The delicate balance between the advantageous and detrimental effects of free radicals is clearly an important aspect of life. While the controlled production of reactive oxygen species has an important role in various physiological processes such as different receptor-mediated signaling pathways, immune response, programmed cell death, plant growth etc. [37], enhanced generation of radicals appears to be highly correlated with many pathophysiological events such as neurodegenerative diseases (Alzheimer disease, Amyotrophic lateral sclerosis, Down's syndrome), malignancy, diabetes mellitus, arthrosclerosis, ageing [37], and sepsis [37,38]. Therefore, to have an internal understanding of biosystems, it is important to investigate and quantify the production of radicals and to understand mechanisms through which reactive species are generated and through which they affect cells, tissues and the functioning of organisms. ...
The choice of the spin-trap that is to be applied in any EPR study represents the crossroad between a comprehensive investigation and an "ordinary" quantification of production of radicals. So, the scope of our study was to compare the performance of different spin-traps for qualitative analysis of radical-generating systems, and their ability to recognize previously unnoticed radicals. In addition, we present a brief account of the difficulties involved in the detection of oxygen-centered radicals in chemical and biological systems accompanied by the rationale for using the EPR spin-trapping technique in quantitative studies of such reactive species. Certain technical aspects of EPR experiments related to efficient trapping of free radicals in biochemical systems are also discussed. As an example we present here results obtained using EPR spectroscopy and the spin-trap DEPMPO, which show that the Fenton reaction, as well as various biological systems generate a previously unappreciated hydrogen (*H) atom.
... Since free radicals are species that contain one or more unpaired electrons, most of them are relatively reactive and capable of oxidizing biomolecules. Due to this property, an uncontrolled generation of radicals is associated with various pathophysiologies such as neurodegenerative diseases (4), malignancy (5), atherosclerosis (6), diabetes (7), sepsis (8), pregnancy complications (9), and also the aging process (10). However, in the 70's and the 80's, the science of free radicals has entered a new era with first reports on the the advantageous effects of reactive species (11,12). ...
Electron Paramagnetic Resonance - A Powerful Tool of Medical Biochemistry in Discovering Mechanisms of Disease and Treatment Prospects
In pathophysiological conditions related to oxidative stress, the application of selected antioxidants could have beneficial effects on human health. Electron paramagnetic resonance (EPR) spectroscopy is a technique that provides unique insight into the redox biochemistry, due to its ability to: (i) distinguish and quantify different reactive species, such as hydroxyl radical, superoxide, carbon centered radicals, hydrogen atom, nitric oxide, ascorbyl radical, melanin, and others; (ii) evaluate the antioxidative capacity of various compounds, extracts and foods; (iii) provide information on other important parameters of biological systems. A combination of EPR spectroscopy and traditional biochemical methods represents an efficient tool in the studies of disease mechanisms and antioxidative therapy prospects, providing a more complete view into the redox processes in the human organism.
... Free radicals can provoke damage to proteins, nucleic acids, and membrane lipids. Elevated cellular levels of reactive oxygen species have been associated with many age-related health problems including neurodegenerative diseases, malignancy, arthrosclerosis, and heart diseases (1,2) as well as other pathophysiological conditions such as diabetes, ischemia/reperfusion injury (1), sepsis (3) and some complications during pregnancy (4). ...
... The most basic mechanisms include (i) stockpiling iron when it is available in ferritin-or bacterioferritinbased iron reserve complexes for use when iron is scarce (20) and (ii) retrenchment, where physiological activities are reduced until the iron scarcity is relieved (21). Bacteria also utilize high-affinity siderophore-based iron capture methods, where low-molecularmass (Ͻ1.5-kDa) iron-binding molecules, having iron binding constants on the order of 10 20 to 10 50 (22,23), are secreted. When iron is bound to these siderophores, high-affinity membrane transporters (e.g., FepA, with an affinity constant for ferric enterobactin of Ͻ0.2 nM [24]) transport the iron into the microorgan-ism's interior, where it is transferred to iron-trafficking proteins (25)(26)(27). ...
Iron bioavailability is a major limiter of bacteria growth in mammalian host tissue and thus represents an important area of study. Escherichia coli K-12 metabolism was studied at four levels of iron limitation in chemostats using physiological and proteomic analyses. The data documented an E. coli acclimation gradient where progressively more severe iron scarcity resulted in a larger percentage of substrate carbon being directed into an overflow metabolism accompanied by a decrease in biomass yield on glucose. Acetate was the primary secreted organic byproduct for moderate levels of iron limitation but as stress increased, the metabolism shifted to secrete primarily lactate (∼ 70% of catabolized glucose carbon). Proteomic analysis reinforced the physiological data and quantified relative increases in glycolysis enzyme abundance and decreases in tricarboxylic acid (TCA) cycle enzyme abundance with increasing iron-limitation stress. The combined data indicated that E. coli responds to limiting iron by investing the scarce resource into essential enzymes, at the cost of catabolic efficiency (i.e. down regulating high ATP-yielding pathways containing enzymes with large iron requirements like the TCA cycle). Acclimation to iron-limited growth was contrasted experimentally with acclimation to glucose-limited growth to identify both general and nutrient-specific acclimation strategies. While the iron-limited cultures maximized biomass yields on iron and increased expression of iron acquisition strategies, the glucose-limited cultures maximized biomass yields on glucose and increased expression of carbon acquisition strategies. This study quantifies ecologically-competitive acclimations to nutrient limitations, yielding knowledge essential for understanding medically-relevant bacterial responses to host and to developing intervention strategies.
... In addition to acting as a cytotoxic agonist, heme is a putative source of labile iron that can promote microbial growth, thus limiting host resistance to infection (49). Hmox1-deficient mice accumulate heme in plasma and develop tissue iron overload following M. avium infection (Fig. 4A), which could contribute to the higher pathogen load observed in Hmox1 Ϫ/Ϫ than in Hmox1 ϩ/ϩ mice (Fig. 1D). ...
Heme oxygenases (HO) catalyze the rate-limiting step of heme degradation. The cytoprotective action of the inducible HO-1
isoform, encoded by the Hmox1 gene, is required for host protection against systemic infections. Here we report that upregulation of HO-1 expression in
macrophages (Mϕ) is strictly required for protection against mycobacterial infection in mice. HO-1-deficient (Hmox1−/−) mice are more susceptible to intravenous Mycobacterium avium infection, failing to mount a protective granulomatous response and developing higher pathogen loads, than infected wild-type
(Hmox1+/+) controls. Furthermore, Hmox1−/− mice also develop higher pathogen loads and ultimately succumb when challenged with a low-dose aerosol infection with Mycobacterium tuberculosis. The protective effect of HO-1 acts independently of adaptive immunity, as revealed in M. avium-infected Hmox1−/− versus Hmox1+/+ SCID mice lacking mature B and T cells. In the absence of HO-1, heme accumulation acts as a cytotoxic pro-oxidant in infected
Mϕ, an effect mimicked by exogenous heme administration to M. avium-infected wild-type Mϕ in vitro or to mice in vivo. In conclusion, HO-1 prevents the cytotoxic effect of heme in Mϕ, contributing critically to host resistance to Mycobacterium infection.
... There is evidence that PCT levels are higher in infections caused by Gram-negative than those caused by Gram-positive bacteria 55 and it seems to be more specific than PCR 18,56 . Ferritin, serum iron binding capacity, and transferrin are tests that must be interpreted with caution in septic patients, since all may be changed due to the presence of high levels of hepcidin 57 . Ferritin is an acute phase protein that is usually elevated in sepsis and reflects the status of iron stores. ...
Sepsis is a common condition encountered in hospital environments. There is no effective treatment for sepsis, and it remains an important cause of death at intensive care units. This study aimed to discuss some methods that are available in clinics, and tests that have been recently developed for the diagnosis of sepsis.
A systematic review was performed through the analysis of the following descriptors: sepsis, diagnostic methods, biological markers, and cytokines.
The deleterious effects of sepsis are caused by an imbalance between the invasiveness of the pathogen and the ability of the host to mount an effective immune response. Consequently, the host's immune surveillance fails to eliminate the pathogen, allowing it to spread. Moreover, there is a pro-inflammatory mediator release, inappropriate activation of the coagulation and complement cascades, leading to dysfunction of multiple organs and systems. The difficulty achieve total recovery of the patient is explainable. There is an increased incidence of sepsis worldwide due to factors such as aging population, larger number of surgeries, and number of microorganisms resistant to existing antibiotics.
The search for new diagnostic markers associated with increased risk of sepsis development and molecules that can be correlated to certain steps of sepsis is becoming necessary. This would allow for earlier diagnosis, facilitate patient prognosis characterization, and prediction of possible evolution of each case. All other markers are regrettably constrained to research units.
... On the other hand, the other role of hepcidin as an ironregulator to prevent the export of cellular iron would be in line with the iron-withholding strategy of the host, which is an extension of the innate immune system (Beck et al., 2002). The main purpose of this strategy is to minimize pathogenic access to iron, which is a vital cofactor for various biological processes including proliferation (Bullen et al., 2000). The up-regulation of hepcidin expression in the liver upon infection was generally consistent with previous studies of HAMP2-type subunit expression in M. chrysops (Shike et al., 2002), Acanthopagrus schlegelii (black porgy) (Yang et al., 2007 ), Paralichthys olivaceus (Japanese flounder ) (Kim et al, 2005), Pagrus auriga (redbanded seabream) (MartinAntonio et al., 2009), Chrysophrys major (red sea bream) (Chen et al., 2005) and O. fasciatus (Cho et al., 2009). ...
A major challenge in the aquaculture industry is the prevalence of diseases that results in large economic losses annually. Therefore, a detailed understanding of the components in the fish immune system is necessary to develop novel methods for disease management. Hepcidin is an acute phase protein that possesses antimicrobial properties and functions as a major iron regulator. The aims of this study were to generate the complete coding sequence of hepcidin in the Asian seabass (Lates calcarifer) and to characterize its expression during an immune response. The complete open reading frame of L. calcarifer hepcidin (Lcahep), which consisted of 279 nucleotides was amplified, cloned and sequenced. The phylogenetic reconstruction using Maximum Likelihood clustered Lcahep with other seawater fish and separated it from the freshwater fish. Results of the analysis also provides additional support for the hypothesis that the evolution of hepcidin is influenced by the environment in which it is found. Additionally, the multiple sequence alignment and phylogenetic analysis indicated that Lcahep is a HAMP2-type hepcidin subunit. This was further supported by expression profiles of Lcahep in various tissues from immune-challenged L. calcarifer. The rapid up-regulation of Lcahep in the liver, spleen, kidney and gill tissues suggested an important role for Lcahep in the innate immune response against pathogens. Taken together, the results of this study clarified the identity of a hepcidin subunit in L. calcarifer and indicated an important role for this gene in the early stages of infection.
... The ability to acquire iron plays a role in the outcome of bacterial infections (Griffiths 1993, Tai et al. 1993, Furman et al. 1994, Rouquette et al. 1995, Conte et al. 1996, Tsolis et al. 1996, Ward et al. 1996, Cornelissen et al. 1998, Rozalska et al. 1998). Yet, besides this long-standing (Bullen 1974, 1981, 1985, Bullen et al. 2000 correlation, many fundamental mechanistic questions about bacterial iron uptake remain unanswered. At the cell surface, Gram-negative bacteria contain numerous receptors for uptake of ferric complexes that provide the recognition function of the complicated multicomponent active transport systems of which they are a part. ...
Listeria monocytogenes, the causative agent of listeriosis, is a virulent foodborne Gram-positive bacterial pathogen, with 20-30% mortality. It has a broad ability to transport iron, either in the form of ferric siderophores, or by extracting it from mammalian iron binding proteins. In this review we focus on the mechanisms of ferric siderophore and haem transport into the listerial cell. Despite the fact that it does not synthesize siderophores, L. monocytogenes transports ferric siderophores in the wild environment by the actions of cytoplasmic membrane ABC-transporter systems. The bacterium acquires haem, on the other hand, by two mechanisms. At low (nanomolar) concentrations, sortase B-dependent, peptidoglycan-anchored proteins scavenge the iron porphyrin in human or animal tissues, and transfer it to the underlying ABC-transporters in the cytoplasmic membrane for uptake. At concentrations at or above 50 nM, however, haem transport becomes sortase-independent, and occurs by direct interactions of the iron porphyrin with the same ABC-transporter complexes. The architecture of the Gram-positive cell envelope plays a fundamental role in these mechanisms, and the haem acquisition abilities of L. monocytogenes are an element of its ability to cause infectious disease.
... On the other hand, overproduction or inefficient removal of • O 2 and H 2 O 2 by scavenging enzymes (superoxide dismutase, catalase, peroxidase) as well as the generation of highly reactive ▪ OH were shown to lead to the damage of biomolecules and cellular membranes in a process known as oxidative stress 4,5 . It has been associated with many health problems including malignancy, neurodegenerative diseases, arthrosclerosis, heart diseases, ischemia/reperfusion injury 5 , sepsis 6 , diabetes, and some pregnancy complications 7 . Under such pathophysiological conditions, supplementation of antioxidants in rebalancing disturbed oxidative status could be a very beneficial component of treatment or diet 8 . ...
Electron paramagnetic resonance (EPR) spin-trapping and spin-probing techniques were applied to determine antioxidant activity
of extracts of catkin, leaves, and spiny burs of Castanea sativa against physiologically relevant reactive species—superoxide and hydroxyl radical generated in simple chemical systems and
hydrogen peroxide applied on erythrocytes. Efflux of K+ was used as a marker of membrane integrity. Chemical composition of extracts was analyzed using HPLC/DAD and LC/MS. Extracts
showed high antioxidative capacity against superoxide but lower activity against hydroxyl radical. They protected fluidity
and integrity of membranes of erythrocytes exposed to hydrogen peroxide. Levels of derivatives of ellagitannins showed positive
correlation with the antioxidative activity of extracts. Therefore, ellagitannins from chestnut extracts could represent easily
accessible natural antioxidants and beneficial component of human diet in pathophysiological conditions related to oxidative
stress. In conclusion, EPR spectroscopy represents a valuable tool for evaluation of antioxidant activity in both hydrophilic
and lipophilic media.
... RBC lysis results in the release of MetHb into the plasma [64], refl ecting the severity of sepsis [66]. An increased level of free MetHb in the plasma may have several propagating eff ects on sepsis development: (i) it leads to increased availability of iron to pathogens, which may fuel their proliferation [67]; (ii) it has pro-infl ammatory eff ects by stimulating interleukins (IL-6 and IL-8) and E-selectin [68]; and (iii) MetHb is an activator of NF-κB [64], which may lead to further iNOS expression, thus closing a • NO-generating loop (Figure 2). ...
The pathogenesis of sepsis and its progression to multiple organ dysfunction syndrome and septic shock have been the subject of investigations for nearly half a century. Controversies still exist with regard to understanding the molecular pathophysiology of sepsis in relation to the complex roles played by reactive oxygen species, nitric oxide, complements and cytokines. In the present review we categorise the key turning points in sepsis development and outline the most probable sequence of events leading to cellular dysfunction and organ failure under septic conditions. We have applied an integrative approach in order to fuse current state-of-the-art knowledge about redox processes involving hydrogen peroxide, nitric oxide, superoxide, peroxynitrite and hydroxyl radical, which lead to mitochondrial respiratory dysfunction. Finally, from this point of view, the potential of redox therapy targeting sepsis is discussed.
Iron is irreplaceably required for animal and human cells as it provides the activity center for a wide variety of essential enzymes needed for energy production, nucleic acid synthesis, carbon metabolism and cellular defense. However, iron is toxic when present in excess and its uptake and storage must, therefore, be tightly regulated to avoid damage. A growing body of evidence indicates that iron dysregulation leading to excess quantities of free reactive iron is responsible for a wide range of otherwise discrete diseases. Iron excess can promote proliferative diseases such as infections and cancer by supplying iron to pathogens or cancer cells. Toxicity from reactive iron plays roles in the pathogenesis of various metabolic, neurological and inflammatory diseases. Interestingly, a common underlying aspect of these conditions is availability of excess reactive iron. This underpinning aspect provides a potential new therapeutic avenue. Existing hematologically used iron chelators to take up excess iron have shown serious limitations for use but new purpose-designed chelators in development show promise for suppressing microbial pathogen and cancer cell growth, and also for relieving iron-induced toxicity in neurological and other diseases. Hepcidin and hepcidin agonists are also showing promise for relieving iron dysregulation. Harnessing iron-driven reactive oxygen species (ROS) generation with ferroptosis has shown promise for selective destruction of cancer cells. We review biological iron requirements, iron regulation and the nature of iron dysregulation in various diseases. Current results pertaining to potential new therapies are also reviewed.
Background
The association of ageing with increased sepsis mortality is well established. Nonetheless, current investigations on the influence of age on host response aberrations are largely limited to plasma cytokine levels while neglecting other pathophysiological sepsis domains like endothelial cell activation and function, and coagulation activation. The primary objective of this study was to gain insight into the association of ageing with aberrations in key host response pathways and blood transcriptomes in sepsis.
Methods
We analysed the clinical outcome (n = 1952), 16 plasma biomarkers providing insight in deregulation of specific pathophysiological domains (n = 899), and blood leukocyte transcriptomes (n = 488) of sepsis patients stratified according to age decades. Blood transcriptome results were validated in an independent sepsis cohort and compared with healthy individuals.
Results
Older age was associated with increased mortality independent of comorbidities and disease severity. Ageing was associated with lower endothelial cell activation and dysfunction, and similar inflammation and coagulation activation, despite higher disease severity scores. Blood leukocytes of patients ≥ 70 years, compared to patients < 50 years, showed decreased expression of genes involved in cytokine signaling, and innate and adaptive immunity, and increased expression of genes involved in hemostasis and endothelial cell activation. The diminished expression of gene pathways related to innate immunity and cytokine signaling in subjects ≥ 70 years was sepsis-induced, as healthy subjects ≥ 70 years showed enhanced expression of these pathways compared to healthy individuals < 50 years.
Conclusions
These data demonstrate age-associated differences in the host response to sepsis and suggest that age should be considered in patient selection in future sepsis trials targeting the immune system and/or the endothelial cell response.
The present-day data on possible pathways of iron influence on human immune response and susceptibility to infections have been considered. The article describes changes of immunologic resistance in conditions of low iron level and mechanisms of iron status disturbance as a consequence of immunostimulation.
Introduction
The WHO recommends daily oral iron supplementation for 12 weeks in women and adolescents where anaemia prevalence is greater than 40%. However, if iron deficiency is not a major cause of anaemia, then, at best, untargeted iron supplementation is a waste of resources; at worst, it could cause harm. Further, different forms of iron with varying bioavailability may present greater risks of harm.
Methods and analysis
A 12-week three-arm, double-blind, randomised controlled supplementation trial was conducted in Cambodia to determine if there is potential harm associated with untargeted iron supplementation. We will recruit and randomise 480 non-pregnant women (ages 18–45 years) to receive one of three interventions: 60 mg elemental iron as ferrous sulfate (the standard, commonly used form), 18 mg ferrous bisglycinate (a highly bioavailable iron amino acid chelate) or placebo. We will measure ferritin concentrations (to evaluate non-inferiority between the two forms of iron), as well as markers of potential harm in blood and stool (faecal calprotectin, gut pathogen abundance and DNA damage) at baseline and 12 weeks. Mixed-effects generalised linear models will be used to assess the effect of iron on ferritin concentration and markers of potential harm at 12 weeks.
Ethics and dissemination
Ethical approval was obtained from the University of British Columbia Clinical Research Ethics Board (H18-02610), the Children's and Women's Health Centre of British Columbia Research Ethics Board (H18-02610) and the National Ethics Committee for Health Research in Cambodia (273-NECHR). Findings will be published in peer-reviewed journals, presented to stakeholders and policymakers globally and shared within participants’ communities.
Trial registration number
ClinicalTrials.gov Registry ( NCT04017598 ).
A study of the main indicators of red blood (RBC, HGB, HCT, MCV, MCH) and the concentration of EPO, sTfR in 9 cancer patients with anemic syndrome (AS) against sepsis was carried out. Among them, patients with chronic disease anemia (ACh), with normocytic, normochromic characteristics of red blood cells and low hematocrit predominated. In 2 patients, microcytosis and erythrocyte hypochromia were noted, the concentration of sTfR was significantly higher than normal (0.9 ± 0.07 μg / ml), amounted to 2.7 μg / ml in one of them and 1.9 μg / ml in the other, which testified to t iron deficiency erythropoiesis (IDE) on the background of the ACh,. In 7 patients with ACh without IDE, sTfR values were within the normal range (0.1-1.2) μg / ml, the median was 0.5 μg/ml. In all patients with sepsis, the production of EPO was inadequate for the severity of the AS, to a lesser extent in patients with IDE. The average EPO production in the group was 19.4 ± 5.1 (7.7-52.8) mU / ml, median = 12.1 mE / ml. Further studies of EPO, sTfR are planned in order to determine their role in therapeutic tactics in the correction of AS in cancer patients with sepsis.
Sepsis is a systemic process with multifactorial pathophysiology that affects most animal species. It is responsible for high rates of morbidity and mortality. This work aimed to study the biochemical and neuroendocrine changes of the sepsis process in Piaractus mesopotamicus after Aeromonas hydrophila inoculation analyzing changes in blood leukocyte and differences in neuroendocrine-biochemical modulation using RNA-seq. Fish showed hypercortisolemia, inhibition of glucose absorption, followed by hypocortisolemia and then hyperglycemia. Thyroid hormones (T3 and T4) showed immediate decrease in serum and T4 increased 6 hours post-inoculation (HPI). Sepsis-induced hormonal alterations triggered changes in the metabolic pathways increasing protein and lipid catabolism, use of transient anaerobic glycolysis and liver injury. A reference transcriptome was constructed based on blood leukocytes from P. mesopotamicus. The assembly resulted in total 266,272 contigs with a N50 of 2,786 bp. There was a reorganization of plasma membrane of leukocytes at the beginning of the septic process with increased expression of neuroendocrine receptors and with continuous flow of neurotransmitters, hormones and solutes with compensatory regulation at 6 HPI. Three and nine HPI seemed to be critical, the expression of a number of transcription factors was increased, including the modulatory DEGs related to glucocorticoid and thyroid hormones induced and suppressed (FDR<0.05). Neuroendocrine modulation can regulate leukocytes and biochemical parameters of peripheral blood, being important sources for the study of the pathophysiology of sepsis. These finding highlights the importance of further studies focusing on biochemical-neuroendocrine changes in blood leukocytes and systemic sepsis.
Iron is an essential nutrient for bacterial survival and thus higher iron levels may precipitate bacterial infections. We investigated the association between the serum iron level and prognosis in patients with sepsis by using the single-centre Medical Information Mart for Intensive Care III (MIMIC-III) database. Sepsis patients with iron parameters measured on ICU admission were included and stratified according to quartiles of serum iron levels. A total of 1,891 patients diagnosed with sepsis according to the Sepsis-3 criteria were included in this study, 324 of whom were septic shock. After adjusting for confounding variables, higher iron quartile was associated with an increase in 90-day mortality in the Cox regression analysis. Moreover, a stepwise increase in the risk of 90-day mortality was observed as the quartiles of serum iron levels increased in the patients with sepsis. In conclusion, higher serum iron levels were independently associated with increased 90-day mortality in this large cohort of patients with sepsis.
Recently the role of phenolic compounds as protective dietary constituents has become an increasingly important area of human nutrition research. So far the application of extract of sweet chesnut in diet and therapy was poorly studied. Samples of catkins of sweet chestnut and grafted Italian marrone cultivar have been collected in Bosnia and Herzegovina. The samples were milled for further analysis. After the addition of 250 ml of 50% ethanol to 50 g of each sample, extraction of the ethanol dissolving compounds was performed by ultrasound (30 min). The samples were filtrated and dried by evaporation under vacuum at 313 K. The extracts were kept at 193 K. With intention to simulate metabolism of tannins in human intestine and to simplify the analysis, chestnut extracts were submitted to methanolysis. The identification of the constituents of the extracts after methanolysis was performed by LC/MS and HPLC/DAD. The antioxidative properties of extracts was invetigated by application of electron paramagnetic resonance (EPR) technique. In the other hand, the disc-diffusion method was used as a test for antimicrobial activity. The identified compounds in examinated extracts could be classified as ellagic acid or its derivatives, gallic acid derivates, flavonoids (quercetin, kaempferol, isorhamnetin) and coumaric acid methyl ester. The highest content of gallic acid derivates was obtained in extract of grafted Italian marrone cultivar 136.8 mg/g, experessed as gallic acid per g of dry extract. Condensed and hydrolysable tannins are potentially more potent antioxidants than simple monomeric phenolics. The most prominent antioxidant activity against superoxide radical was detected for the extract of catkins of grafted Italian marrone (RI=85%). Total level of derivatives of ellagitannins showed statistically significant positive correlation with antioxidative activity of extracts against superoxide. The test extracts demonstrated significant antimicrobial activity, especially against both Gram-negative (Salmonella typhimurium) and Gram-positive (Micrococcus pyogenes var. albus and Staphylococcus aureus) bacteria. The growing interest in the substitution of synthetic food antioxidants by natural ones has fostered research on vegetable sources and the screening of raw materials for identifying new antioxidants. We found that Castanea sativa Mill. catkins extracts could be one with promising characteristics. Also, analysing extracts possesses great antimicrobial activity.
Diarrhoegenic Escherichia coli are of a broad variety. A clear understanding of the virulence/pathogenicity determinants of pathogenic Escherichia coli is important as they affect a large section of the population in the tropical and developing areas of the world. Faecal contamination of food and water is the major route of infection for humans. Based on minor differences in surface structure chemistry there are over 800 serotypes of Escherichia coli. Diagnostic methods used nowadays focus on the detection of either specific toxins such as heat stable (ST), heat labile (LT) and their specific attributes for example colonization factors (CF's) and specific target genes for example eaeA, which permit the identification of the corresponding pathotype. Classification of E. coli is an evolving science and more categories of pathogenic E. coli will be identified in the future. The virulence determinants in E. coli play the major role in infections in both humans and animals. Journal of Tropical Microbiology and Biotechnology Vol. 3(1) 2007: pp. 29-37
Background In-home iron fortification for infants in developing countries is recommended for control of anaemia, but low absorption typically results in >80% of the iron passing into the colon. Iron is essential for growth and virulence of many pathogenic enterobacteria. We determined the effect of high and low dose in-home iron fortification on the infant gut microbiome and intestinal inflammation.
Methods We performed two double-blind randomised controlled trials in 6-month-old Kenyan infants (n=115) consuming home-fortified maize porridge daily for 4 months. In the first, infants received a micronutrient powder (MNP) containing 2.5 mg iron as NaFeEDTA or the MNP without iron. In the second, they received a different MNP containing 12.5 mg iron as ferrous fumarate or the MNP without the iron. The primary outcome was gut microbiome composition analysed by 16S pyrosequencing and targeted real-time PCR (qPCR). Secondary outcomes included faecal calprotectin (marker of intestinal inflammation) and incidence of diarrhoea. We analysed the trials separately and combined.
Results At baseline, 63% of the total microbial 16S rRNA could be assigned to Bifidobacteriaceae but there were high prevalences of pathogens, including Salmonella Clostridium difficile, Clostridium perfringens, and pathogenic Escherichia coli. Using pyrosequencing, +FeMNPs increased enterobacteria, particularly Escherichia/Shigella (p=0.048), the enterobacteria/bifidobacteria ratio (p=0.020), and Clostridium (p=0.030). Most of these effects were confirmed using qPCR; for example, +FeMNPs increased pathogenic E. coli strains (p=0.029). +FeMNPs also increased faecal calprotectin (p=0.002). During the trial, 27.3% of infants in +12.5 mgFeMNP required treatment for diarrhoea versus 8.3% in −12.5 mgFeMNP (p=0.092). There were no study-related serious adverse events in either group.
Conclusions In this setting, provision of iron-containing MNPs to weaning infants adversely affects the gut microbiome, increasing pathogen abundance and causing intestinal inflammation.
Trial registration number NCT01111864.
Dibromocarboxyarsenazo (DBCA) was used to complex Fe and Cu ions at pH 6.22, and complexes Cu(DBCA) and Fe(DBCA) were formed. Fe ion replaced Cu competitively from its dinuclear complex Cu(DBCA)Cu to form the heterodinuclear complex, Cu(DBCA)Fe. The light‐absorption ratio variation approach has been applied to the direct determination of Fe ions with a high selectivity and good sensitivity using heterodinuclear replacement complexation. The limit of detection of Fe is only 2.5 ng/mL. The results from the analyses of five Huangpu River (Shanghai) cross‐section samples indicate that Fe ions are from 5.0 to 39.2 μg/L with the recovery rates between 85.5 and 111.5%.
Neonatal sepsis is one of the most fulminating conditions in neonatal intensive care units. Anti-pathogen and supportive care are administered routinely, but do not deliver satisfactory results. In addition, the efforts to treat neonatal sepsis with anti-inflammatory agents have generally shown to be futile. The accumulating data imply that intracellular redox changes intertwined into neonatal sepsis redox cycle represent the main cause of dysfunction of mitochondria and cells in neonatal sepsis. Our aim here is to support the new philosophy in neonatal sepsis treatment which involves the integration of mechanisms that are responsible for cellular dysfunction and organ failure, the recognition of the most important targets, and the selection of safe agents that can stop the neonatal sepsis redox cycle by hitting the hot spots. Redox-active agents that could be beneficial for neonatal sepsis treatment according to these criteria include lactoferrin, interleukin-10, zinc and selenium supplements, ibuprofen, edaravone, and pentoxifylline.
Diprivan has earned a prominent place in the armamentarium of anesthesiologists, owing to its favorable pharmacokinetic profile, the clearheaded and slightly euphoric emergence associated with Diprivan, and useful secondary properties such as reduction of postoperative nausea and vomiting. Diprivan also has many shortcomings, including several directly related to the Intralipid vehicle: the ability to support bacterial growth, pain on injection, hypertriglyceridemia with prolonged infusions, and the potential for Intralipid to compromise the immune response.
Many companies have attempted to improve on the original propofol formulation. AstraZeneca added EDTA to reduce the risk of infection, and serendipitously may have found a formulation that actually improves survival in critically ill patients. Gensia Sicor added metabisulfite to the formulation. Despite an initial furor over the lack of clinical safety data the product appears to be safe, effective, and therapeutically equivalent within the scope of its narrowed labeling. Braun developed propofol in a medium-chain/long-chain triglyceride formulation. This formulation appears to provide identical pharmacokinetics and pharmacodynamics while reducing pain on injection. More complex formulation changes include nanoparticulate and cyclodextrin technologies, or administering propofol as a water-soluble prodrug. These latter approaches will not be commercially available for several years.
The interest in altered formulations is a testament to the quality of propofol as an anesthetic. These diverse development programs also demonstrate encouraging interest in pharmaceutical companies in improving the anesthetic experience and clinical outcome for our surgical patients.
Using electron paramagnetic resonance (EPR) spectroscopy, antioxidant properties of chestnut extracts have been investigated as a source of phenolic compounds. In addition to their high antioxidant activities against hydroxyl and organic free (DPPH) radicals, phe-nolics showed to be potent protectors of membranes from lipid peroxidation. To the best of our knowledge, the ability of an antioxidant to overcome body's refractory response to-wards antioxidant supplementation has been examined for the first time. The water solu-ble extracts obtained from leaves, catkins, and outer brown peel of Castanea sativa Mill. showed high antioxidant activity in scavenging · OH and DPPH radical. All extracts, except for sweet chestnut catkins, showed the ability to protect liposomes from peroxidation. Pheno-lic compounds, as active antioxidants, have the ability to enter and protect cell membranes from lipid peroxidation, thus overcoming the body's refractory response to the antioxidant supplements in the diet. It is shown that phenolics are easily accessible natural antioxi-dants that can be used as food supplements or for the treatment of pathophysiological conditions related to oxidative stress.
The effects of iron-dextran and the iron chelator desferrioxamine B mesylate (Desferal) on the course and outcome of experimental yersiniosis were investigated. Yersinia enterocolitica strains representing the three leading serogroups pathogenic for humans, O3, O8 and O9, were studied. In mice, iron-dextran reduced the median lethal dose of intraperitoneally administered Y. enterocolitica O3 and O9 ca. 10-fold, whereas Desferal reduced this value more than 100,000-fold. Experiments in which Y. enterocolitica was given orally to mice and intraconjunctivally to guinea pigs confirmed that Desferal markedly increased the susceptibility of animals to yersiniosis. Although serogroup O8 yersiniae were inherently more virulent for laboratory animals, they were less affected by Desferal than were O3 or O9 strains. In vitro experiments indicated that Desferal promoted growth of Y. enterocolitica under iron-limiting conditions and suggested that the enhanced virulence of O8 yersiniae may be due to their comparatively low requirement for iron. The adverse effect of Desferal on the course of experimental infection with Y. enterocolitica may partly explain the heightened susceptibility of iron-overloaded patients to systemic yersiniosis.
Vibrio vulnificus is killed by normal human blood but grows rapidly in blood from patients with hemochromatosis. It also grows in normal blood if the saturation of the transferrin is increased or if hematin, which contains iron, is added. It is suggested that the increased availability of iron in the blood of patients with chronic iron overload is responsible for their enhanced susceptibility to infection with V vulnificus.
(Arch Intern Med. 1991;151:1606-1609)
Enterochelin (enterobactin), the cyclic trilactone of N-(2,3-dihydroxybenzoyl)-L-serine 6, an important enterobacterial iron-transporting compound, has been synthesised from N,N-dibenzyl-L-serine 2 in four steps. The protected amino acid was oligomerised using N,N–dicyclohexylcarbodiimide in a high-dilution procedure yielding a mixture of di-, tri- and tetra-lactones. The trilactone 3b was deprotected by hydrogenolysis and the resultant amine 4 was acylated with 2,3-dibenzyloxybenzoyl chloride to yield hexa-O-benzylenterochelin 5. This upon hydrogenolysis gave enterochelin in moderate yield.
The influence of pH changes upon the iron-binding properties of transferrin was investigated in the absence of chelating agents. The effects were demonstrated by spectrophotometry, gel filtration, and by studies of the intermolecular transfer of 59Fe from transferrin to conalbumin.
At pH values below 6.7, diferric transferrin readily loses iron. The monoferric molecule, which is relatively resistant to acid dissociation, is preferentially formed. A temporary reduction of pH provides a simple method for selectively attaching iron to one metal-binding site, and allows double isotopic labelling of the transferrin molecule. This technique may permit further investigation of the physiological properties of the two iron-binding sites.
Iron is essential for most living things. The importance of the metal lies in its remarkable capacity to engage in electron transport reactions in biological systems (Neilands, 1974). From the point of view of infection, a clear distinction must be made between the quantity of iron present in body fluids and its availability to bacteria. In the living body, iron is not freely available. The bulk of the metal is locked up in ferritin, hemosiderin, myoglobin, and in the hemoglobin in red cells (Lanzkowsky, 1976). The iron-binding proteins, transferrin and lactoferrin, which possess only a minute fraction of the total body iron, are normally only partly saturated with Fe and have an exceptionally high association constant of about 1036 for the metal. This means that the amount of free iron in equilibrium with these proteins is only about 10−8 M, which is far too low for normal bacterial growth. To obtain Fe from normal tissue, bacteria must therefore possess iron chelating agents with association constants similar to those of transferrin and lactoferrin. In injured or dead tissue the situtation may be very different. For example, the lysis of red cells can provide large amounts of Fe for those bacteria that can assimilate heme compounds.
The bactericidal power of fresh human plasma against Klebsiella pneumoniae and Escherichia coli was extremely sensitive to changes in Eh and pH. At a high Eh (approx. +200 mV) the bacteria were destroyed, but rapid regrowth occurred when the Eh was lowered to approx. -400 mV. Abolition of the bactericidal effect was also produced by adding ferric iron at a high Eh (approx. +200 mV). Lowering the pH to 6.50 reduced or prevented the bactericidal effect. These results are probably related to the availability of iron for bacterial growth, and could be important for understanding the development of infection in injured or diseased tissue.
Vibrio vulnificus is killed by normal human blood but grows rapidly in blood from patients with hemochromatosis. It also grows in normal blood if the saturation of the transferrin is increased or if hematin, which contains iron, is added. It is suggested that the increased availability of iron in the blood of patients with chronic iron overload is responsible for their enhanced susceptibility to infection with V vulnificus.
Patients with burns are unusually susceptible to bacterial infections, but so far there is no satisfactory explanation for this lack of resistance. Since resistance to infection involves many different mechanisms, examination of individual components of the immune system may not sufficiently explain the underlying reasons for increased susceptibility. The use of whole blood for antibacterial tests has the advantage that all the immune systems present in that fluid compartment can take part in the bactericidal effect. Tests with Klebsiella pneumoniae and Staphylococcus aureus showed no evidence that the bactericidal power of the blood and plasma of patients with burns was less than that of normal control plasma. This suggests that the solution to the problem of increased susceptibility to infection in patients with burns does not lie with the blood but must be looked for elsewhere.
Many of the biochemical events of wound healing are prisoners of the victim's physiologic state. Although the initial local events of inflammation occur normally in any viable tissue, the subsequent reparative capacities of macrophages, fibroblasts, and endothelial cells are seriously impaired by any compromise of local perfusion and oxygenation. In particular, the bacteriocidal capacities of granulocytes are heavily dependent on local oxygenation/perfusion, nutrition, and endocrine status. This article depicts the local mechanisms of repair with special attention to the means by which physiologic and nutritional support at the clinical level influence repair, even to a point at which wound healing may exceed contemporary expectations. Without appropriate physiologic, nutritional, and endocrine support, wound healing often fails totally. It is now possible, although not always easy, to achieve optimal physiologic support.
Blood-culture procedures must be designed to overcome the intermittency and low order of magnitude of most bacteremias and
fungemias and to inhibit any antimicrobial properties or components of the blood. Among the several variables affecting yields,
the volume of blood cultured appears to be most important. It is recommended that at least 10ml, and preferably 20–30 ml,
of blood be obtained for each of two to three separate cultures. More than three separate blood cultures per septic episode
is rarely necessary. Other issues involve the systems used for blood culture and the procedures used for their examination.
The virulence of Pseudomonas aeruginosa can be enhanced by passage in mice or rabbits. Enhanced virulence has some specificity for the host in which the passage is done. Experimental infection in the peritoneal cavity of cannulated rabbits has shown that the injection of iron compounds can lead to a rapid and fatal growth of an otherwise nonlethal dose of bacteria. In vitro the unsaturated iron-binding proteins present in the peritoneal fluid can halve the growth rate of P. aeruginosa. The restricted rate of growth is restored to normal if the iron-binding proteins are saturated with iron. Exactly the same results are achieved with purified transferrin. Both fatal and nonfatal infections with P. aeruginosa cause a sharp fall in the percentage of saturation with Fe of the plasma and peritoneal fluid. In both normal and infected animals the peritoneal fluid is invariably less saturated than the plasma. Specific antiserum not only protects against death but also against the fall in iron saturation of the plasma and peritoneal fluid. In both fatal and nonfatal infections a high proportion of viable bacteria are unphagocytized in the peritoneal cavity.
Human polymorphonuclear neutrophils (PMN) were made anaerobic by nitrogen washout (oxygen saturation <1%, Eh < -42 mV at pH 7.0), and the ability of the cells to kill bacteria was assayed and compared to the bactericidal activity of aerobic PMN. Anaerobic PMN were able to kill Staphylococcus epidermidis, Enterococcus, viridans streptococci, Pseudomonas aeruginosa, Peptostreptococcus anaerobius, Bacteroides fragilis, Clostridium perfringens, and Peptococcus magnus normally. Organisms that were not killed normally by anaerobic PMN included Staphylococcus aureus (strains Wood 46 and 502a), Escherichia coli, Serratia marcescens, Klebsiella pneumoniae, Proteus vulgaris, and Salmonella typhimurium. These findings suggest that mechanisms other than those dependent on hydrogen peroxide may be important in the killing of some bacteria.
Studies using an experimental model of the mouse and Candida albicans as the challenge organism attempted to define better the mechanism of nonspecific resistance to infection induced by bacterial endotoxins. In vitro studies showed a positive correlation between the growth of C. albicans in serum from mice obtained at daily intervals for 10 days after endotoxin or saline injection and the percentage iron saturation of the serum. In vivo studies in which one of four different concentrations of iron as ferric ammonium citrate was injected into control and endotoxin-treated mice at the time of challenge with C. albicans showed that the rate of mortality of the mice was directly related to the concentration of iron injected. The endotoxin-induced nonspecific resistance was negated and reversed by iron administration. These studies demonstrate that changes in iron metabolism induced by bacterial endotoxin are a key factor in the mechanism of resistance to C. albicans infection in mice.
plasma and has the electrophoretic mobility of a beta-l-globulin. Nor- mally only about one third of the transferrin is saturated with iron.1 In 1946, Schade and Caroline2 demonstrated the bacteriostatic effect of transferrin. This in vitro antimicrobial power is depressed by free iron and enhanced by an increase in iron-binding capacity.3 Fresh human serum has also been shown to be fungistatic.4#{176} This inhibition of fungal growth can be overcome by the addition of iron.7'8 Thus, the fungistatic principle in normal human serum may be transferrin. Serum from patients with acute leukemia has been shown to have a mark- edlv reduced capacity to inhibit the growth of yeasts such as Candida.#{176}'1#{176} The present report demonstrates that many patients with acute myeloblastic leukemia have elevated serum iron levels and nearly totally saturated serum iron-binding capacities. Some of these patients had systemic candidiasis, ele- vated Candida agglutination titers and positive anticandidal precipitin tests. It is postulated that these aberrations in iron metabolism in patients with acute leukemia may be causally related to the development of candida and other fungal infections.1' In vivo and in vitro studies support this hypothesis.
1Circumstantial evidence suggests that the ability of the host to prevent the uptake of iron by pathogenic bacteria may constitute an important means of defence. A detailed biochemical study of the way antisera exert their antibacterial effects and the possible involvement of iron has now been initiated.2Work with Pasteurella septica antiserum has revealed a totally unsuspected way in which antiserum and complement exert their antibacterial effects. The process is very quick and specific and results in the cessation of bacterial multiplication; cells in stasis then appear to be killed by the operation of a secondary event. The inhibitory process operates by affecting the biochemistry of the bacterial cell leading first to an inhibition of net RNA synthesis and then to an inhibition of all macromolecular synthesis.3The presence of free iron in the serum did not prevent the initiation of the inhibition but it did allow macromolecular synthesis, cell multiplication and rapid growth to be resumed later. In contrast, the presence of haematin in the serum allowed the cells to continue multiplying in the presence of antiserum without delay. Addition of haematin to bacteria which had been inhibited by antiserum restored net RNA synthesis immediately. Net protein synthesis and multiplication were restarted within 15–20 min and DNA synthesis in 40 min.
An important concern that has received little attention is the possible increased susceptibility to bacterial infections of patients infused with cell-free haemoglobin-based blood substitutes. We show that pyridoxalated polymerised human haemoglobin promotes fulminating Escherichia coli septicaemia in mice, which draws attention to the potential danger of such products in the clinic.
To evaluate the short-term and long-term outcomes of patients with suspected bacteremia, we performed a prospective cohort study.
Clinical data were collected within 24 hours of initial culture from a random sample of 1516 episodes in which blood cultures were performed in an urban tertiary care hospital. One hundred forty-two patients with bacteremia were compared with two comparison groups: (1) 142 randomly selected patients with negative cultures, matched in age within 5 years, gender, severity of underlying disease, and presence of major comorbidity, and (2) all 155 patients with contaminant cultures. The main outcome measures were death, death secondary to bacteremia, and major complications.
In the 439 patients, there were 142 deaths (32%), 114 at 1 year (26%) and 46 within 30 days (11%). Mortality at 30 days was most highly correlated with predicted fatality of underlying disease: 48% for the 65 patients with a rapidly fatal disease, 9% for the 156 patients with an eventually fatal disease, and 0.5% for the 217 patients with no fatal disease. In a Cox survival analysis, the risk ratio associated with bacteremia was 1.6 (95% confidence interval, 1.0 to 2.4) vs the comparison groups. When we performed time-dependent Cox analyses in which the hazard ratio was allowed to change at 30 days, we found that the risk ratios associated with bacteremia were 2.3 (95% confidence interval, 1.2 to 4.4) for the first 30 days, and 1.3 (95% confidence interval, 0.76 to 2.1) after 30 days.
We conclude that this population has a high mortality, which is strongly correlated with severity of underlying disease. Short-term mortality was higher in patients with bacteremia even after controlling for severity of illness, but the increase in risk was present only during the first month and most deaths occurred in patients with a rapidly fatal disease.
The diagnostic significance of pH, pO2 (partial pressure of oxygen), and pCO2 (partial pressure of carbon dioxide) was studied in pus, peritoneal fluid, and drainage fluid obtained during or after abdominal surgery. Measurements of these fluids in 59 patients with clinically and bacteriologically documented abdominal or anorectal infection (median pH: 6.75, median pO2: 28 mm Hg, median pCO2: 89 mm Hg) differed significantly (p < 0.001) from data of 105 patients undergoing elective laparotomy for a reason other than infection (median pH: 7.49, median pO2: 144 mm Hg, median pCO2: 92 mm Hg). The combined use of a threshold criterion for pH and pO2 allowed for excellent discrimination between infected (pH less than 7.1, pO2 less than 49 mm Hg) and noninfected patients, with positive and negative predictive values of 98% and 99%, respectively. In conclusion, conditions prevailing during standard in vitro susceptibility tests more closely reflect physiologic conditions as opposed to the conditions prevailing at the site of abdominal infections. Measurements of pH and pO2 allow for an easy, quick, sensitive, and specific diagnosis of bacterial abdominal infection.
To evaluate the diagnostic yield of blood cultures obtained in a surgical intensive care unit (ICU) and to assess factors potentially influencing yield.
Retrospective, descriptive study.
Surgical ICU in a university hospital.
All patients who had a blood culture obtained during their admission to the trauma/neurosurgical ICU of Presbyterian University Hospital from January 1, 1993 to December 31, 1993.
Blood culture isolates were categorized as pathogens or contaminants and overall diagnostic yield was determined. Blood cultures were positive for pathogens in 4.6% of all culture episodes, while contaminants were isolated in 5.5% of all culture episodes. A total of 23 true bacteremias were identified in 21 patients, for an overall rate of bacteremia of 3.6 per 100 admissions (5.9 per 1,000 patient days). Concurrent antibiotics were being used at the time of blood culture in 65.3% of all culture episodes. The yield for pathogens was significantly lower (2.2%) when cultures were obtained on antibiotics compared with culture episodes obtained off antibiotics (6.4%) (p < .05). Single-set blood culture episodes were obtained in approximately 32% of all culturing episodes with the overall yield for pathogens of these culturing episodes lower (2.9%) than that of multiple-set culture episodes (5.3%) (p = NS).
Blood culture yield in this surgical ICU was relatively low in comparison with other published studies. The data further suggest that concurrent use of systemic antibiotics and inappropriate or excessive culturing may negatively influence blood culture yield.
During the past decade much effort has been devoted worldwide to limiting the spread of methicillin-resistant Staphylococcus aureus. However, the recent emergence of almost untreatable vancomycin-resistant enterococci has led to a new and unexpected public health problem in hospitals and the community. Moreover, the threat of transfer of glycopeptide resistance to S aureus means that development of alternative antimicrobial strategies has become urgent. Whereas major advances have been made in our understanding of methicillin and vancomycin resistance mechanisms, we still need to identify the sources and reservoirs of the genetic determinants of resistance and to discover how they disseminate in the environment. The outcome of the battle between antimicrobials and bacteria is still uncertain, but the challenge is worth meeting.
Between a quarter and half of all patients with sepsis who die have other ultimately fatal illnesses or injuries. Thus, perhaps only 50 percent of all deaths attributed to sepsis are caused exclusively by sepsis, but it is often difficult to determine a single cause of death in patients with multiple-organ-system failure. Aside from the use of antibiotics, treatment approaches continue to focus on eradicating infection and supporting failing organs so that the patient can heal. Mortality due to sepsis may be declining because of improvements in organ-system support and prevention of complications, even in the absence of any single therapeutic advance in the treatment of sepsis. Our enhanced understanding of the biochemistry of sepsis should soon result in the development of effective specific therapies.
SUlMMARY The bacteriostatic effect of specific antiserum on Clostridiuna wekhii type A was profoundly influenced by the pH and E, of the medium. With suitable concentrations of specific antiserum relatively high pH and E, values led to a well-marked inhibition of growth accompanied by destruction of the bacteria. A relatively low pH or E, led to a decrease or abolition of the inhibitory power of the specific antiserum. Neither com- plement nor properdin appeared to be involved in the bacteriostatic effect. Organisms. Clostdiurn welchii type A strain ~~2726 was used for all the experi- ments in vitro. Strain CN 2726 and type A strain CN 1491 were both used for immu- nization in preparing the antiserum. Both strains were obtained from the Wellcome Research Laboratories (Beckenham, Kent). Spec@ CZo&ridiuna zoelchii antisemcm. One antiserum (P 10) was used for all the experiments; this was obtained from a pony after eight courses of immunization against Clostridium welchii type A. Formolieed whole cultures of strain ~~2726 were used for the first seven courses; for the eighth course the pony was injected intra,mwularly with a mixture of concentrated toxin from strains ~~2726 and CN14t91, and subcutaneously with washed and formalized organisms of strain ~~2726. The antitoxin content of the antiserum in unitslml. was as follows;
Iron and Infection. Molecular, Physiological, and Clinical Aspects, 2nd edition The role of Eh, pH and iron in the bactericidal power of human plasma
- C G Ward
- J J Bullen
- J J Bullen
- E Griffiths
Ward C.G., Bullen J.J., in: Bullen J.J., Griffiths E. (Eds.), Iron and Infection. Molecular, Physiological, and Clinical Aspects, 2nd edition. Wiley, Chichester, 1999, pp. 369–450. [9] Bullen, J.J., Spalding P.B., Ward C.G., Roger S.H.J., The role of Eh, pH and iron in the bactericidal power of human plasma, FEMS Microbiol. Lett. 94 (1992) 47–52.
Howbadarebacteremia and sepsis?
- W Batesd
- E Preussk
- H Leet
BatesD.W.,PreussK.E.,LeeT.H.,Howbadarebacteremia and sepsis?, Arch. Int. Med. 155 (1995) 593–598.
The problem of sepsis. An expert report of the European Society of Intensive Care Medicine
- Vincent
Treating patients with severe sepsis
- Wheeler
How bad are bacteremia and sepsis?
- Bates