Production of carcinogenic acetaldehyde by Candida albicans from patients with potentially malignant oral mucosal disorders

OBJECTIVES: Production of carcinogenic acetaldehyde by Candida has been suggested to contribute to epithelial dysplasia and oral carcinogenesis. Oral lichen planus (OLP), oral lichenoid lesion (OLL) and oral leukoplakia (OL) are potentially carcinogenic oral diseases where colonisation by Candida is common, but acetaldehyde production by Candida has not been studied. STUDY DESIGN: Acetaldehyde production in ethanol (11 mM), glucose (100 mM), ethanol–glucose (11 mM and 100 mM) or red wine (1200 mM ethanol) incubation by Candida albicans from patients with OLL (n = 6), OLP (n = 16), OL (n = 6) and controls (n = 6) was measured by gas chromatography. Participants completed a questionnaire regarding their smoking habits and alcohol consumption. RESULTS: All Candida albicans isolates produced potentially carcinogenic levels of acetaldehyde (>100 lM) in all incubations containing ethanol. The control group isolates produced the highest acetaldehyde levels. Isolates from smokers produced more acetaldehyde in all incubations than those from non-smokers. The difference was significant in ethanol–glucose incubation. Isolates from patients who were both smokers and drinkers produced the highest amounts when incubated in ethanol, ethanol– glucose and wine. CONCLUSIONS: Candida albicans isolated from potentially carcinogenic oral diseases can produce mutagenic amounts of acetaldehyde. Cigarette smoking and alcohol consumption may favour adaptational changes resulting in the upregulation of candidal acetaldehyde metabolism.peer-reviewe

In vitro adhesion of oral Candida species to denture materials

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Ibrexafungerp, a Novel Triterpenoid Antifungal in Development for the Treatment of Mold Infections

Molds are ubiquitous in the environment, and immunocompromised patients are at substantial risk of morbidity and mortality due to their underlying disease and the resistance of pathogenic molds to currently recommended antifungal therapies. This combination of weakened-host defense, with limited antifungal treatment options, and the opportunism of environmental molds renders patients at risk and especially vulnerable to invasive mold infections such as Aspergillus and members of the Order Mucorales. Currently, available antifungal drugs such as azoles and echinocandins, as well as combinations of the same, offer some degree of efficacy in the prevention and treatment of invasive mold infections, but their use is often limited by drug resistance mechanisms, toxicity, drug-drug interactions, and the relative paucity of oral treatment options. Clearly, there is a need for agents that are of a new class that provides adequate tissue penetration, can be administered orally, and have broad-spectrum efficacy against fungal infections, including those caused by invasive mold organisms. Ibrexafungerp, an orally bioavailable glucan synthase inhibitor, is the first in a new class of triterpenoid antifungals and shares a similar target to the well-established echinocandins. Ibrexafungerp has a very favorable pharmacokinetic profile for the treatment of fungal infections with excellent tissue penetration in organs targeted by molds, such as the lungs, liver, and skin. Ibrexafungerp has demonstrated in vitro activity against Aspergillus spp. as well as efficacy in animal models of invasive aspergillosis and mucormycosis. Furthermore, ibrexafungerp is approved for use in the USA for the treatment of women with vulvovaginal candidiasis. Ibrexafungerp is currently being evaluated in clinical trials as monotherapy or in combination with other antifungals for treating invasive fungal infections caused by yeasts and molds. Thus, ibrexafungerp offers promise as a new addition to the clinician's armamentarium against these difficult-to-treat infections.Experiments reported in this manuscript were funded by Scynexis and support for mucormycosis research was provided by the NIH/NIAID under Contract No. HHSN272201700039I (Task order A34-HHSN27200003).S

Unraveling the crosstalk between cell sheets of human adipose stem cells and keratinocytes

We have previously shown that 3D constructs of human adipose stem cells (hASCs) cell sheets led to the formation of de novo hair follicles and rete-ridges like structures. An up-regulation of keratinocyte growth factor (KGF) was also observed in the experimental condition in relation to the control groups. We hypothesized that the natural adhesive character of the cell sheets promoted the direct interaction between the host and the transplanted cells1. In this sense, the present work aims at elucidating this communication between hASCs and human keratinocytes (hKC) and determining the extent of its mediation by KGF. In an in vitro scratch assays we showed that the secretome of hASCs in contact with hKC promotes cell migration and closure of the scrape. Moreover, when KGF-antibody was added diminished hKC migration was observed, suggesting that KGF might be one of the key cytokines involved in the interaction with hASCs. Furthermore, in order to assess the communication via gap junctions (GJ), a calcein-AM transfer assay was carried out in the presence/absence of a GJ inhibitor. The transference of the dye from hASCs to adjacent hKC, confirmed both by fluorescence microscopy and flow cytometry, showed that these cells also communicate via GJ. Moreover while hKCs expressed connexin (cx)43 and cx26, highly expressed at the wound margins, hASCs were only positive for cx43  as shown by immunocytochemistry and flow cytometry. Finally, the direct communication between transplanted hASCs cell sheets and hKC at the wound margins is being addressed in a human ex-vivo skin model with an artificial wound, to better mimic the previous in vivo conditions and confirm our hypothesis. So far we were able to demonstrate that hASCs and hKCs communicate directly through cx43 and indirectly via KGF secreted by hASCs, which promote KCs migration. (1)       Cerqueira, M. T.; Pirraco, R. P.; Santos, T. C.; Rodrigues, D. B.; Frias, A. M.; Martins, A. R.; Reis, R. L.; Marques, A. P.; Cerqueira   Pirraco, RP,  Santos, TC,  Frias, AM,  Martins, AR,  Reis, RL, Marques, AP, M. T. Biomacromolecules 2013, 14, 3997â 4008.    Portuguese Foundation for Science and Technology (FCT) for MTC (SFRH/BPD/96611/2013),RPP(SFRH/BPD/101886/2014)info:eu-repo/semantics/publishedVersio

Consensus-based antimicrobial resistance and stewardship competencies for UK undergraduate medical students.

BACKGROUND: In the UK there is limited coverage of antimicrobial stewardship across postgraduate curricula and evidence that final year medical students have insufficient and inconsistent antimicrobial stewardship teaching. A national undergraduate curriculum for antimicrobial resistance and stewardship is required to standardize an adequate level of understanding for all future doctors. OBJECTIVES: To provide a UK national consensus on competencies for antimicrobial resistance and stewardship for undergraduate medical education. METHODS: Using the modified Delphi method over two online survey rounds, an expert panel comprising leads for infection teaching from 25 UK medical schools reviewed competency descriptors for antimicrobial resistance and stewardship education. RESULTS: There was a response rate of 100% with all 28 experts who agreed to take part completing both survey rounds. Following the first-round survey, of the initial 55 descriptors, 43 reached consensus (78%). The second-round survey included the 12 descriptors from the first round in which agreement had not been reached, four amended descriptors and 12 new descriptors following qualitative feedback from the panel members. Following the second-round survey, a total of 58 consensus-based competency descriptors within six overarching domains were identified. CONCLUSIONS: The consensus-based competency descriptors defined here can be used to inform standards, design curricula, develop assessment tools and direct UK undergraduate medical education

Polymerase Chain Reaction on Respiratory Tract Specimens of Immunocompromised Patients to Diagnose Pneumocystis Pneumonia: A Systematic Review and Meta-analysis.

BACKGROUND: This meta-analysis examines the comparative diagnostic performance of polymerase chain reaction (PCR) for the diagnosis of Pneumocystis pneumonia (PCP) on different respiratory tract samples, in both human immunodeficiency virus (HIV) and non-HIV populations. METHODS: A total of 55 articles met inclusion criteria, including 11 434 PCR assays on respiratory specimens from 7835 patients at risk of PCP. QUADAS-2 tool indicated low risk of bias across all studies. Using a bivariate and random-effects meta-regression analysis, the diagnostic performance of PCR against the European Organisation for Research and Treatment of Cancer-Mycoses Study Group definition of proven PCP was examined. RESULTS: Quantitative PCR (qPCR) on bronchoalveolar lavage fluid provided the highest pooled sensitivity of 98.7% (95% confidence interval [CI], 96.8%-99.5%), adequate specificity of 89.3% (95% CI, 84.4%-92.7%), negative likelihood ratio (LR-) of 0.014, and positive likelihood ratio (LR+) of 9.19. qPCR on induced sputum provided similarly high sensitivity of 99.0% (95% CI, 94.4%-99.3%) but a reduced specificity of 81.5% (95% CI, 72.1%-88.3%), LR- of 0.024, and LR+ of 5.30. qPCR on upper respiratory tract samples provided lower sensitivity of 89.2% (95% CI, 71.0%-96.5%), high specificity of 90.5% (95% CI, 80.9%-95.5%), LR- of 0.120, and LR+ of 9.34. There was no significant difference in sensitivity and specificity of PCR according to HIV status of patients. CONCLUSIONS: On deeper respiratory tract specimens, PCR negativity can be used to confidently exclude PCP, but PCR positivity will likely require clinical interpretation to distinguish between colonization and active infection, partially dependent on the strength of the PCR signal (indicative of fungal burden), the specimen type, and patient population tested

Risk Factors for Intra-Abdominal Candidiasis in Intensive Care Units: Results from EUCANDICU Study

Introduction: Intra-abdominal infections represent the second most frequently acquired infection in the intensive care unit (ICU), with mortality rates ranging from 20% to 50%. Candida spp. may be responsible for up to 10–30% of cases. This study assesses risk factors for development of intra-abdominal candidiasis (IAC) among patients admitted to ICU. Methods: We performed a case–control study in 26 European ICUs during the period January 2015–December 2016. Patients at least 18 years old who developed an episode of microbiologically documented IAC during their stay in the ICU (at least 48 h after admission) served as the case cohort. The control group consisted of adult patients who did not develop episodes of IAC during ICU admission. Matching was performed at a ratio of 1:1 according to time at risk (i.e. controls had to have at least the same length of ICU stay as their matched cases prior to IAC onset), ICU ward and period of study. Results: During the study period, 101 case patients with a diagnosis of IAC were included in the study. On univariate analysis, severe hepatic failure, prior receipt of antibiotics, prior receipt of parenteral nutrition, abdominal drain, prior bacterial infection, anastomotic leakage, recurrent gastrointestinal perforation, prior receipt of antifungal drugs and higher median number of abdominal surgical interventions were associated with IAC development. On multivariate analysis, recurrent gastrointestinal perforation (OR 13.90; 95% CI 2.65–72.82, p = 0.002), anastomotic leakage (OR 6.61; 95% CI 1.98–21.99, p = 0.002), abdominal drain (OR 6.58; 95% CI 1.73–25.06, p = 0.006), prior receipt of antifungal drugs (OR 4.26; 95% CI 1.04–17.46, p = 0.04) or antibiotics (OR 3.78; 95% CI 1.32–10.52, p = 0.01) were independently associated with IAC. Conclusions: Gastrointestinal perforation, anastomotic leakage, abdominal drain and prior receipt of antifungals or antibiotics may help to identify critically ill patients with higher probability of developing IAC. Prospective studies are needed to identify which patients will benefit from early antifungal treatment

Interaction between M-Like Protein and Macrophage Thioredoxin Facilitates Antiphagocytosis for Streptococcus equi ssp. zooepidemicus

Streptococcus equi ssp. zooepidemicus (S. zooepidemicus, S.z) is one of the common pathogens that can cause septicemia, meningitis, and mammitis in domesticated species. M-like protein (SzP) is an important virulence factor of S. zooepidemicus and contributes to bacterial infection and antiphagocytosis. The interaction between SzP of S. zooepidemicus and porcine thioredoxin (TRX) was identified by the yeast two-hybrid and further confirmed by co-immunoprecipitation. SzP interacted with both reduced and the oxidized forms of TRX without inhibiting TRX activity. Membrane anchored SzP was able to recruit TRX to the surface, which would facilitate the antiphagocytosis of the bacteria. Further experiments revealed that TRX regulated the alternative complement pathway by inhibiting C3 convertase activity and associating with factor H (FH). TRX alone inhibited C3 cleavage and C3a production, and the inhibitory effect was additive when FH was also present. TRX inhibited C3 deposition on the bacterial surface when it was recruited by SzP. These new findings indicated that S. zooepidemicus used SzP to recruit TRX and regulated the alternative complement pathways to evade the host immune phagocytosis

O-Antigen Delays Lipopolysaccharide Recognition and Impairs Antibacterial Host Defense in Murine Intestinal Epithelial Cells

Although Toll-like receptor (TLR) 4 signals from the cell surface of myeloid cells, it is restricted to an intracellular compartment and requires ligand internalization in intestinal epithelial cells (IECs). Yet, the functional consequence of cell-type specific receptor localization and uptake-dependent lipopolysaccharide (LPS) recognition is unknown. Here, we demonstrate a strikingly delayed activation of IECs but not macrophages by wildtype Salmonella enterica subsp. enterica sv. (S.) Typhimurium as compared to isogenic O-antigen deficient mutants. Delayed epithelial activation is associated with impaired LPS internalization and retarded TLR4-mediated immune recognition. The O-antigen-mediated evasion from early epithelial innate immune activation significantly enhances intraepithelial bacterial survival in vitro and in vivo following oral challenge. These data identify O-antigen expression as an innate immune evasion mechanism during apical intestinal epithelial invasion and illustrate the importance of early innate immune recognition for efficient host defense against invading Salmonella