Mechanisms underlying the exquisite sensitivity of Candida albicans to combinatorial cationic and oxidative stress that enhances the potent fungicidal activity of phagocytes

This is the final version. Available on open access from the American Society for Microbiology via the DOI in this recordImmune cells exploit reactive oxygen species (ROS) and cationic fluxes to kill microbial pathogens, such as the fungus Candida albicans. Yet, C. albicans is resistant to these stresses in vitro. Therefore, what accounts for the potent antifungal activity of neutrophils? We show that simultaneous exposure to oxidative and cationic stresses is much more potent than the individual stresses themselves and that this combinatorial stress kills C. albicans synergistically in vitro. We also show that the high fungicidal activity of human neutrophils is dependent on the combinatorial effects of the oxidative burst and cationic fluxes, as their pharmacological attenuation with apocynin or glibenclamide reduced phagocytic potency to a similar extent. The mechanistic basis for the extreme potency of combinatorial cationic plus oxidative stress—a phenomenon we term stress pathway interference— lies with the inhibition of hydrogen peroxide detoxification by the cations. In C. albicans this causes the intracellular accumulation of ROS, the inhibition of Cap1 (a transcriptional activator that normally drives the transcriptional response to oxidative stress), and altered readouts of the stress-activated protein kinase Hog1. This leads to a loss of oxidative and cationic stress transcriptional outputs, a precipitous collapse in stress adaptation, and cell death. This stress pathway interference can be suppressed by ectopic catalase (Cat1) expression, which inhibits the intracellular accumulation of ROS and the synergistic killing of C. albicans cells by combinatorial cationic plus oxidative stress. Stress pathway interference represents a powerful fungicidal mechanism employed by the host that suggests novel approaches to potentiate antifungal therapy.IMPORTANCE The immune system combats infection via phagocytic cells that recognize and kill pathogenic microbes. Human neutrophils combat Candida infections by killing this fungus with a potent mix of chemicals that includes reactive oxygen species (ROS) and cations. Yet, Candida albicans is relatively resistant to these stresses in vitro. We show that it is the combination of oxidative plus cationic stresses that kills yeasts so effectively, and we define the molecular mechanisms that underlie this potency. Cations inhibit catalase. This leads to the accumulation of intracellular ROS and inhibits the transcription factor Cap1, which is critical for the oxidative stress response in C. albicans. This triggers a dramatic collapse in fungal stress adaptation and cell death. Blocking either the oxidative burst or cationic fluxes in human neutrophils significantly reduces their ability to kill this fungal pathogen, indicating that combinatorial stress is pivotal to immune surveillance.Biotechnology and Biological Sciences Research Council (BBSRC)Wellcome TrustEuropean CommissionNIAI

Hypothermic cardiac arrest far away from the center providing rewarming with extracorporeal circulation

A 41-year-old man suffered hypothermic cardiac arrest after water immersion and was transported to our university hospital by ambulance helicopter for rewarming on cardiopulmonary bypass. He resumed spontaneous cardiac activity 6 h 52 min after cardiac arrest and recovered completely

Cellular responses of Candida albicans to phagocytosis and the extracellular activities of neutrophils are critical to counteract carbohydrate starvation, oxidative and nitrosative stress

Acknowledgments We thank Alexander Johnson (yhb1D/D), Karl Kuchler (sodD/D mutants), Janet Quinn (hog1D/D, hog1/cap1D/D, trx1D/D) and Peter Staib (ssu1D/D) for providing mutant strains. We acknowledge helpful discussions with our colleagues from the Microbial Pathogenicity Mechanisms Department, Fungal Septomics and the Microbial Biochemistry and Physiology Research Group at the Hans Kno¨ll Institute (HKI), specially Ilse D. Jacobsen, Duncan Wilson, Sascha Brunke, Lydia Kasper, Franziska Gerwien, Sea´na Duggan, Katrin Haupt, Kerstin Hu¨nniger, and Matthias Brock, as well as from our partners in the FINSysB Network. Author Contributions Conceived and designed the experiments: PM HW IMB AJPB OK BH. Performed the experiments: PM CD HW. Analyzed the data: PM HW IMB AJPB OK BH. Wrote the paper: PM HW OK AJPB BH.Peer reviewedPublisher PD

Burn wounds infected with Pseudomonas aeruginosa triggers weight loss in rats

BACKGROUND: Despite dramatic improvements in the management of burns, infection still remains a serious risk for the burn patient. The aim of this study was to shed light on the impact of acute burn injury with or without infection on cytokine profiles. METHODS: Sprague-Dawley rats (n = 21) were randomized into three groups: 1) burn only 2) burn and infection or 3) sham burn. Weight was monitored and blood was collected for cytokine ELISA, LPS quantification, and peripheral blood analysis. Animals were sacrificed either after 6 or 12 days. RESULTS: Infected animals showed substantial weight loss until day 6 post-burn as compared to burn alone. Endotoxin and TNF-α levels were elevated early in the infected burn group within 48 hours post-burn. In contrast, significant up-regulation of the anti-inflammatory cytokine IL-10 occurred later in the clinical course and was associated with the recovery from weight loss. CONCLUSION: Our results suggest that in the presence of infection, you get a SIRS response possibly due to transient endotoxemia that is only seen in the infection group. In contrast, both burn and infection get a late IL-10 (CARS) response, which is then associated with a return to normal weight in the infection group

Pulpal sequelae after trauma to anterior teeth among adult Nigerian dental patients

<p>Abstract</p> <p>Background</p> <p>Epidemiological studies show that about 11.6% to 33.0% of all boys and about 3.6% to 19.3% of all girls suffer dental trauma of varying severity before the age of 12 years. Moderate injuries to the periodontium such as concussion and subluxation are usually associated with relatively minor symptoms and hence may go unnoticed by the patient or the dentist, if consulted. Patients with these kinds of injuries present years after a traumatic accident most of the time with a single discoloured tooth. This study sets out to document the incidence of various posttraumatic sequelae of discoloured anterior teeth among adult Nigerian dental patients.</p> <p>Methods</p> <p>One hundred and sixty eight (168) traumatized discoloured anterior teeth in 165 patients were studied. Teeth with root canal treatment were excluded from the study. Partial obliteration was recorded when the pulp chamber or root canal was not discernible or reduced in size on radiographs, total obliteration was recorded when pulp chamber and root canal were not discernible. A retrospective diagnosis of concussion was made from patient's history of trauma to the tooth without abnormal loosening, while subluxation was made from patient's history of trauma to the tooth with abnormal loosening.</p> <p>Results</p> <p>Of the 168 traumatized discoloured anterior teeth, 47.6% and 31.6% had partial and total obliteration of the pulp canal spaces respectively, 20.8% had pulpal necrosis. Concussion and subluxation injuries resulted more in obliteration of the pulp canal space, while fracture of the teeth resulted in more pulpal necrosis (p < 0.001). Injuries sustained during the 1^stand 2^nddecade of life resulted more in obliteration of the pulp canal space, while injuries sustained in the 3^rddecade resulted in more pulpal necrosis.</p> <p>Conclusion</p> <p>Calcific metamorphosis developed more in teeth with concussion and subluxation injuries. Pulpal necrosis occurred more often in traumatized teeth including fractures.</p

The neural basis of video gaming

Video game playing is a frequent recreational activity. Previous studies have reported an involvement of dopamine-related ventral striatum. However, structural brain correlates of video game playing have not been investigated. On magnetic resonance imaging scans of 154 14-year-olds, we computed voxel-based morphometry to explore differences between frequent and infrequent video game players. Moreover, we assessed the Monetary Incentive Delay (MID) task during functional magnetic resonance imaging and the Cambridge Gambling Task (CGT). We found higher left striatal grey matter volume when comparing frequent against infrequent video game players that was negatively correlated with deliberation time in CGT. Within the same region, we found an activity difference in MID task: frequent compared with infrequent video game players showed enhanced activity during feedback of loss compared with no loss. This activity was likewise negatively correlated with deliberation time. The association of video game playing with higher left ventral striatum volume could reflect altered reward processing and represent adaptive neural plasticity

Risk of malnutrition is associated with mental health symptoms in community living elderly men and women: The Tromsø Study

<p>Abstract</p> <p>Background</p> <p>Little research has been done on the relationship between malnutrition and mental health in community living elderly individuals. In the present study, we aimed to assess the associations between mental health (particularly anxiety and depression) and both the risk of malnutrition and body mass index (BMI, kg/m²) in a large sample of elderly men and women from Tromsø, Norway.</p> <p>Methods</p> <p>In a cross-sectional survey, with 1558 men and 1553 women aged 65 to 87 years, the risk of malnutrition was assessed by the Malnutrition Universal Screening Tool ('MUST'), and mental health was measured by the Symptoms Check List 10 (SCL-10). BMI was categorised into six groups (< 20.0, 20.0-22.4, 22.5-24.9, 25.0-27.4, 27.5-29.9, ≥ 30.0 kg/m²).</p> <p>Results</p> <p>The risk of malnutrition (combining medium and high risk) was found in 5.6% of the men and 8.6% of the women. Significant mental health symptoms were reported by 3.9% of the men and 9.1% of the women. In a model adjusted for age, marital status, smoking and education, significant mental health symptoms (SCL-10 score ≥ 1.85) were positively associated with the risk of malnutrition (odds ratio 3.9 [95% CI 1.7-8.6] in men and 2.5 [95%CI 1.3-4.9] in women), the association was positive also for subthreshold mental health symptoms. For individuals with BMI < 20.0 the adjusted odds ratio for significant mental health symptoms was 2.0 [95% CI 1.0-4.0].</p> <p>Conclusions</p> <p>Impaired mental health was strongly associated with the risk of malnutrition in community living elderly men and women and this association was also significant for subthreshold mental health symptoms.</p

Virulence Characteristics and Genetic Affinities of Multiple Drug Resistant Uropathogenic Escherichia coli from a Semi Urban Locality in India

Extraintestinal pathogenic Escherichia coli (ExPEC) are of significant health concern. The emergence of drug resistant E. coli with high virulence potential is alarming. Lack of sufficient data on transmission dynamics, virulence spectrum and antimicrobial resistance of certain pathogens such as the uropathogenic E. coli (UPEC) from countries with high infection burden, such as India, hinders the infection control and management efforts. In this study, we extensively genotyped and phenotyped a collection of 150 UPEC obtained from patients belonging to a semi-urban, industrialized setting near Pune, India. The isolates representing different clinical categories were analyzed in comparison with 50 commensal E. coli isolates from India as well as 50 ExPEC strains from Germany. Virulent strains were identified based on hemolysis, haemagglutination, cell surface hydrophobicity, serum bactericidal activity as well as with the help of O serotyping. We generated antimicrobial resistance profiles for all the clinical isolates and carried out phylogenetic analysis based on repetitive extragenic palindromic (rep)-PCR. E. coli from urinary tract infection cases expressed higher percentages of type I (45%) and P fimbriae (40%) when compared to fecal isolates (25% and 8% respectively). Hemolytic group comprised of 60% of UPEC and only 2% of E. coli from feces. Additionally, we found that serum resistance and cell surface hydrophobicity were not significantly (p = 0.16/p = 0.51) associated with UPEC from clinical cases. Moreover, clinical isolates exhibited highest resistance against amoxicillin (67.3%) and least against nitrofurantoin (57.3%). We also observed that 31.3% of UPEC were extended-spectrum beta-lactamase (ESBL) producers belonging to serotype O25, of which four were also positive for O25b subgroup that is linked to B2-O25b-ST131-CTX-M-15 virulent/multiresistant type. Furthermore, isolates from India and Germany (as well as global sources) were found to be genetically distinct with no evidence to espouse expansion of E. coli from India to the west or vice-versa

Challenges Using Extrapolated Family-level Macroinvertebrate Metrics in Moderately Disturbed Tropical Streams: a Case-study From Belize

Family-level biotic metrics were originally designed to rapidly assess gross organic pollution effects, but came to be regarded as general measures of stream degradation. Improvements in water quality in developed countries have reignited debate about the limitations of family-level taxonomy to detect subtle change, and is resulting in a shift back towards generic and species-level analysis to assess smaller effects. Although the scale of pollution characterizing past condition of streams in developed countries persists in many developing regions, some areas are still considered to be only moderately disturbed. We sampled streams in Belize to investigate the ability of family-level macroinvertebrate metrics to detect change in stream catchments where less than 30% of forest had been cleared. Where disturbance did not co-vary with natural gradients of change, and in areas characterized by low intensity activities, none of the metrics tested detected significant change, despite evidence of environmental impacts. We highlight the need for further research to clarify the response of metrics to disturbance over a broader study area that allows replication for confounding sources of natural variation. We also recommend research to develop more detailed understanding of the taxonomy and ecology of Neotropical macroinvertebrates to improve the robustness of metric use